Дисертації з теми "Composés antitumoraux"
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1
Gineste, Cyrille. "Vectorisation peptidique de deux composés antitumoraux." Montpellier 1, 2003. http://www.theses.fr/2003MON13508.
Повний текст джерелаАнотація:
La doxorubicine est un antibiotique antinéoplasique majeur, malgré ses effets indésirables dus à son manque de sélectivité pour le tissu tumoral. Dans le but d'améliorer la sélectivité, l'hypothèse de travail a été de vectoriser la doxorubicine par un peptide, substrat d'une enzyme, la Cathepsine D. En effet, cette enzyme est surexprimée dans et autour du tissus tumoral, et l'hydrolyse du substrat doit libérer l'anticancéreux au niveau de la tumeur, et donc limiter sa toxicité. Après avoir sélectionné différents peptides substrats de la Cathepsine D, plusieurs prodrogues de la doxorubicine ont été préparées. Elles se différencient par la taille du peptide substrat et la nature de la tête polaire empêchant la prodrogue de diffuser de manière passive dans les cellules saines. En général, ces prodrogues sont hydrolysées par l'enzyme, mais les fragments libérés ne présentent qu'une faible activité cytotoxique. Plusieurs hypothèses sont évoquées pour expliquer ces résultats. Le concept de prodrogue a été également appliqué avec plus de succès à un phosphonate de vinblastine.
2
Jezequel, Gwenaëlle. "Synthèse et pharmacomodulation de composés antitumoraux naturels à motif hexahydroxanthène." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS424.
Повний текст джерелаАнотація:
Les ORPphilins regroupent plusieurs familles de molécules naturelles, à forte activité cytotoxique qui présentent un mécanisme d'action original, en inhibant OSBP, une protéine responsable du transport intra-cellulaire du cholestérol. Cependant, elles sont toutes difficiles d’accès, que ce soit par extraction à partir des organismes dont elles sont issues ou par synthèse chimique.Les schweinfurthines (SWs), isolées de plantes du genre Macaranga, font partie de ces ORPphilins, et sont étudiées par notre équipe depuis plusieurs années. Lors de ces études, il a notamment été montré qu’un analogue non actif, mais bioprécurseur probable de ces SWs était présent en grande quantité dans ces plantes. Le premier objectif de cette thèse a été de faire l’hémisynthèse des SWs et d’analogues non naturels à partir de ce bioprécurseur.Les SWs sont particulièrement actives sur le glioblastome multiforme (GBM), qui est actuellement de très mauvais pronostic. Le traitement consiste aujourd’hui en une chirurgie suivie d’une radiothérapie combinée à une chimiothérapie utilisant le témozolomide (TMZ), un agent alkylant de l’ADN. De nombreuses résistances au TMZ se développent et les récidives sont fréquentes. Or, il a été montré qu’une molécule duale liant de manière covalente deux molécules anti-cancéreuses présentant un mode d’action complémentaire pouvait présenter une synergie d’effets. Le deuxième objectif de cette thèse a donc été de synthétiser et d’évaluer biologiquement différentes molécules duales SW-TMZ.Enfin, une nouvelle molécule de structure originale a été isolée et identifiée des plantes du genre Macaranga. Ce composé présente une activité cytotoxique sur le glioblastome similaire à celle des SWs, et a la même cible protéique que les ORPphilins. Le dernier volet de cette thèse a eu pour objet la synthèse totale de cette molécule, et d’analogues, leur évaluation biologique et la détermination de premières relations structure-activité sur cette nouvelle série chimique.En conclusion, les travaux menés au cours de cette thèse ont permis la synthèse de molécules cytotoxiques, naturelles ou inspirées de produits naturels, ciblant OSBP. Ces molécules pourront ultérieurement servir d’outils moléculaires pour mettre en lumière leur mécanisme d’action encore mal connus et identifier les liens entre transport du cholestérol et cancerORPphilins are a set of several families of natural molecules with strong cytotoxic activity, that have an original mechanism of action by inhibiting OSBP, a protein responsible for the intracellular transport of cholesterol. However, they are all difficult to access, either by extraction from the organisms from which they are derived or by chemical synthesis.Schweinfurthins (SWs), isolated from plants of the genus Macaranga, are part of these ORPphilins, and have been studied by our team for several years. In these studies, it was shown that a non-active but probable bioprecursor analogue of these SWs was present in large amounts in these plants. The first objective of this thesis was to hemisynthezise SWs, and non-natural analogues from this bioprecursor.SWs are particularly active on multiform glioblastoma, which is currently a very poor prognosis. Today, the treatment consists of surgery followed by radiotherapy combined with chemotherapy using temozolomide (TMZ), an alkylating agent of DNA. Many resistances to TMZ develop and recurrences are frequent. However, it has been shown that a dual molecule covalently binding two anti-cancer molecules with a complementary mode of action may present a synergy of effects. The second objective of this thesis was therefore to synthesize and biologically evaluate different SW-TMZ dual molecules.Finally, a new molecule with an original structure has been isolated and identified from plants of the genus Macaranga. This compound has cytotoxic activity on glioblastoma similar to that of SWs, and has the same protein target as ORPphilins. The last part of this thesis focused on the total synthesis of this molecule, and of analogues, their biological evaluation and the determination of the first structure-activity relationships on this new chemical series.In conclusion, the work carried out during this thesis made it possible to synthesize cytotoxic molecules that are either natural or inspired by natural products, targeting OSBP. These molecules can later be used as molecular tools to highlight their as yet poorly understood mechanism of action and identify the links between cholesterol transport and cancer
3
Clavier, Sylvain. "Recherche de nouveaux agents antitumoraux : synthèse et activité cytotoxique de composés polycycliques à structure benzodioxinique." Orléans, 2001. http://www.theses.fr/2001ORLE2019.
Повний текст джерелаАнотація:
Malgré la découverte de nombreux agents antitumoraux et la mise au point de nouveaux traitements, le cancer reste une des principales causes de décès dans les pays développés. Des travaux antérieurs réalisés au laboratoire ont montré que des composés polycycliques à structure benzo[a]oxanthrène possédaient une activité antitumorale prometteuse. Nous avons donc entrepris diverses pharmacomodulations sur ces hétérocycles afin d'établir de nouvelles relations structure-activité et d'améliorer leur activité antitumorale. Nous avons d'abord introduit plusieurs substituants hydroxyles ou méthoxyles sur le système tétracyclique à structure benzodioxinique, en faisant appel à des réactions de métallation et des couplages catalysés par le palladium. Des modifications de la chaîne latérale aminée ont ensuite été apportées, via des réactions de Heck et Sonogashira réalisées sur un triflate arylique. Les résultats prometteurs des tests pharmacologiques nous ont amenés à élaborer de nouveaux hétérocycles à structure benzo[a]furo[3,2-c]oxanthrène qui possèdent une cytotoxicité significative in vitro sur des cellules leucémiques L1210. Afin de renforcer le phénomène d’intercalation dans l'ADN, des imides hexacycliques à structure naphto[2,3-b][1,4]dioxinique ont été obtenus suivant un schéma réactionnel dont l'étape clé est une réaction de Diels-Alder. La voie de synthèse utilisée a aussi permis d'accéder à des naphto[2,3-b][1,4]dioxines 2,3-disubstituées et des furo[3,4-b]naphto[2,3-e][1,4]dioxines, dérivés inconnus jusqu'à présent. Différents dimères associant deux tétracycles à structure 1,4-benzodioxinique ont été préparés et ont conduit à des composés présentant une cytotoxicité tout à fait notable in vitro. Ces résultats très prometteurs ouvrent de nouvelles perspectives et permettent d'envisager de nouvelles modifications structurales susceptibles d'accroître l'activité de ces hétérocycles.
4
Jacquemard, Ulrich. "Synthèse de nouveaux composés indoliques, carbazoliques, pyridiniques et pyraziniques, à visée antitumorale." Orléans, 2005. http://www.theses.fr/2005ORLE2002.
Повний текст джерелаАнотація:
La recherche de nouvelles substances antitumorales pour combattre le cancer passe souvent par la pharmacomodulation de molécules actives existantes. Ainsi, un analogue indolique de la sampangine comme intercalant de l'ADN, et des dérivés carbazoliques, pyridiniques, pyraziniques et indoliques comme ligands ont fait l'objet de nos travaux. Cet analogue indolique de la sampangine, molécule naturelle, est constitué d'un motif pentacyclique. Nous avons synthétisé une pyridine disubstituée sur les sommets 2 et 4 puis condensé l'indole 3-carbaldéhyde sur le sommet 3. Nous n'avons pas pu générer le cycle quinone par fermeture anionique ou électrophile sur le sommet 2 du motif indolique. Par ailleurs, nous avons élaboré des dérivés constitués de trois hétérocycles, un carbazole central substitué en 3 et 6 par deux noyaux aryliques portant des chaînes hydrophiles. Nous avons remplacé le carbazole central par une pyridine ou une pyrazine. Puis nous avons conservé le noyau pyridinique et fait varier les deux motifs périphériques, synthétisant les (bisindoles)pyridines et les pyridines disubstituées par un motif indolique et un motif arylique. L'évaluation biologique de ces composés a été effectuée.
5
Grig, Alexa Irina-Claudia. "Synthèse et fonctionnalisation d'hétérocycles azotés polycycliques : application à l'obtention de composés antitumoraux." Orléans, 2005. http://www.theses.fr/2005ORLE2003.
Повний текст джерелаАнотація:
Le cancer constitue aujourd'hui la deuxième cause de mortalité dans l'ensemble des pays développés après les maladies cardiovasculaires. De nombreuses équipes de chimistes travaillent sur la synthèse de nouvelles molécules ayant une forte probabilité d'être antitumorales. Dans cette optique, des recherches effectuées au sein de notre Laboratoire ont fait état de la synthèse arynique, de la réactivité et du potentiel caractère anticancéreux d'une nouvelle famille d'antitumoraux – les dihydrodipyridopyrazines. Dans cette thèse, nous réalisons une étude approfondie de la réaction de cyclisation hétarynique et de la fonctionnalisation des dihydrodipyridopyrazines via des réactions de couplage pallado-catalysées et des séquences d'ortho-lithiation. Nous décrivons également l'accès à des dérivés pentacycliques inconnus jusqu'à ce jour qui ont révélé des propriétés chimiques intéressantes. Simultanément, des recherches pharmacologiques ont été menées.
6
Lepifre, Franck. "Elaboration et évaluation des propriétés biologiques de différents systèmes hétérocycliques oxygénés et azotés." Orléans, 2002. http://www.theses.fr/2002ORLE2038.
Повний текст джерелаАнотація:
En dépit de la découverte de nouvelles molécules antitumorales et de la mise au point de nouveaux traitements, le cancer reste une des principales causes de décès dans les pays développés ; la recherche de nouveaux agents anticancéreux plus spécifiques et moins toxiques demeure donc une priorité en ce domaine. Des travaux antérieurs réalisés au laboratoire ont montré que des composés polycycliques à structure benzodioxinique et phénoxazinique possédaient une activité antitumorale prometteuse. Dans le prolongement de cette étude, nous avons élaboré un composé puissant en terme d'inhibition de la prolifération cellulaire aussi bien in vitro (L1210) qu'in vivo (P388). Parallèlement à cette étude, des N-arylbenzoxazolinones et leurs analogues 4-aza ont été préparés et testés in vitro sur les récepteurs PPARs. Ces derniers, régulant la masse des tissus adipeux, constituent des cibles moléculaires dans le traitement de la dyslipidémie, de l'artériosclérose, de l'obésité, du diabète non insulino-dépendant, du cancer, de l'hypertension et de l'infertilité. Un agoniste PPAR? sélectif puissant a pu ainsi être mis en évidence. Ce résultat offre l'opportunité d'étudier le récepteur PPAR?, dont l';ubiquité donne peu d'indices sur ses différentes fonctions. Tous ces composés ont été préparés en faisant appel principalement à des réactions de couplage catalysées par le palladium (0) de type Stille, Suzuki et Sonogashira, et à des réactions de cycloaddition de Diels-Alder. Une extension nouvelle de la réaction de Suzuki mettant en jeu des phosphates vinyliques a été, en particulier, développée et valorisée. Les réactions de couplage, appliquées à divers phosphates vinyliques, ont permis l'élaboration d'ène-carbamates substitués en ? de l'azote, et l'obtention d'hétérocycles azotés de tailles variées. L'étude de la réactivité de ces ène-carbamates a été exploré et une réaction de carbolithiation particulièrement attrayante a été mise en évidence.
7
Ayerbe, Nathalie. "Synthèse et évaluation de l'activité antitumorale de composés à sous-structures benzodioxiniques, benzoxaziniques ou 7-azaindoliques apparentés aux indolocarbazoles." Orléans, 2003. http://www.theses.fr/2003ORLE2009.
Повний текст джерелаАнотація:
Les indolocarbazoles représentent une famille de composés en plein essor à l'heure actuelle en chimiothérapie antitumorale. Il est toujours d'actualité de mettre au point de nouvelles substances chimiques à activité anticancéreuse, dans la mesure où certains des médicaments présents sur le marché montrent des effets secondaires non négligeables, couplés à un phénomène de résistance pléi͏̈otropique. La principale cible cellulaire des indolocarbazoles est la topoisomérase I, enzyme responsable du contrôle topologique de l'ADN (essentiel pour sa transcription et sa réplication). Cependant, beaucoup d'autres systèmes protéiniques, identifiés ou non, peuvent également constituer une cible pour ces composés. A notre connaissance, aucune modification fondamentale, comme le remplacement d'un ou des deux noyaux indoliques de ces systèmes, n'ayant été réalisée, nous nous sommes proposé de préparer des composés dans lesquels l'un ou les deux motifs indoliques seraient remplacés par un noyau benzodioxinique, benzoxazinique, ou 7-azaindolique. Les premiers systèmes à structure bis-benzodioxinique et benzodioxinobenzoxazinique ont été isolés en employant une stratégie de synthèse dont l'étape clef est une réaction de Diels-Alder. Des composés à structure indolobenzodioxinique ont ensuite été préparés via une réaction de couplage de Stille suivie d'une étape de cyclisation par voie photochimique ; une véritable pharmacomodulation a pu être effectuée dans cette série. Enfin, des systèmes à structure indoloazaindolique ont également été préparés. L'ensemble des aglycones obtenus ont fait l'objet de tests pharmacologiques, concernant l'activité cytotoxique sur les cellules L1210 et DU145 et la spécificité sur le cycle cellulaire. Les résultats observés se sont révélés très encourageants, voire remarquables en ce qui concerne deux composés dont les IC50 sont de l'ordre de la nanomolaire. De telles valeurs ne sont en général observées que sur les indolocarbazoles porteurs d'un motif osidique, d'où le caractère particulièrement attractif des molécules considérées. En outre, ces diverses constatations nous ont permis de dégager les premières relations de structure-activité pour ces nouveaux composés, et d'envisager les modifications structurales permettant d'accroître leur activité.
8
Souchard, Jean-Pierre. "Synthèse, propriétés physico-chimiques, et activités pharmacologiques de complexes antitumoraux dérivés du platine (II): relations structure-activité." Toulouse 3, 1990. http://www.theses.fr/1990TOU30128.
Повний текст джерелаАнотація:
L'auteur a mis au point une methode de synthese rapide et fiable des complexes cis-pta#2(ono#2)#2 (a etant une amine ou une pyridine substituee a partir des complexes cis-pta#2i#2 dissous dans l'acetone. L'etude rmn #1h des complexes cis- et trans-pta#2x#2 (x etant un iodure, un chlorure ou un nitrate) a mis en evidence une constante de couplage j(pt-h) permettant d'identifier sans ambiguite l'isomerie des complexes. Les derives cis-pta#2 (ono#2)#2 s'hydrolysent rapidement en solution aqueuse pour donner les complexes diaquo (cis(pta#2(h#2o)#2#2#+, 2 no#3) qui sont stables pendant au moins deux heures. L'influence du pka des ligands a sur la reactivite des complexes diaquo est negligeable. Les coefficients de partage des complexes dichloro cis-pta#2cl#2 et diaquo varient lineairement avec celui des ligands a. Les complexes charges diaquo possedant deux cycloalkylamines ou deux pyridines substituees sont plus lipophiles que le cisplatine qui est neutre. La toxicite des complexes dichloro et diaquo varie lineairement avec leur lipophilie. La charge des complexes diaquo n'est pas un facteur limitant a leur activite antitumorale. Les complexes diaquo possedant deux pyridines substituees ne sont pas antitumoraux alors que les complexes diaquo possedant deux cycloalkylamines le sont. Les complexes cis-bis(amine) diaquoplatine(ii) ont une activite antitumorale et une selectivite optimales si leur lipophilie est comprise entre 1 et 2. L'activite antitumorale des derives cis-bis(amine) dichloroplatine(ii) est maximale lorsque leur lipophilie est de 1,31,0
9
Ainseba, Nabila. "Conception de nouveaux antivasculaires antitumoraux à partir de modèles naturels : synthèse et évaluation biologique." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P612.
Повний текст джерелаАнотація:
Lors de son développement, une tumeur ne peut survivre sans passer par une étape invasive afin de subvenir à ses besoins en nutriment et en oxygène. Cette étape, appelé angiogenèse tumorale, conduit à la formation de vaisseaux sanguins dits « tumoraux », différents des vaisseaux sanguins normaux. Afin de stopper la croissance de la tumeur, il est possible de détruire les vaisseaux sanguins tumoraux formés pendant l’angiogenèse tumorale grâce à des molécules antivasculaires. Ces molécules vont désorganiser la structure du vaisseau et diminuer le flux sanguin au sein de la tumeur pour mener à la nécrose de cette dernière. Parmi ces molécules antivasculaires, la prodrogue phosphate de la combrétastatine A-4 naturelle (CA-4) est le composé actuellement le plus efficace en développement clinique de phase III contre le cancer de la thyroïde. L’objectif de ce travail de thèse a été d’étudier des nouveaux analogues contraints d’aroylindoles et des dérivés de chromène. La série préparée comportera donc la partie triméthoxyphénylique commune à la plupart de ces dérivés, en particulier aux 3-aroylindoles, à savoir des pyrrolo [3,4-a] carbazolediones, et le motif privilégié 2,2-diméthylchromène. Nous avons enfin réalisé l’étude systématique des activités biologiques des molécules synthétisées en déterminant leur cytotoxicité sur mélanome B16, leur aptitude à inhiber la polymérisation de la tubuline et à modifier la morphologie de cellules EA hy926Pas de résumé en anglais
10
Zou, Yu. "Dendrimères et dendrons phosphorés : synthèse, propriétés et applications en nanomédecine." Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://www.theses.fr/2024TLSES093.
Повний текст джерелаАнотація:
L'objectif de ce travail de thèse a été de préparer de nouveaux dendrimères ou dendrons phosphorés, qu'ils soient neutres, cationiques ou anioniques, dans le but d'élargir le panel des applications dans le domaine de la nanomédecine en tant que molécules actives par elles-mêmes ou en association avec certains médicaments. Au chapitre 1, la synthèse d'un nouveau dendrimère phosphoré polycationique comportant en surface 5 groupements pyrrolidinium et une amine protonnée a été menée à bien. Ce dendrimère associé au microRNA-30d permet d'obtenir des polyplexes qui sont transférés dans les cellules cancéreuses. Il a également un bon effet thérapeutique sur les cellules cancéreuses du sein. Au Chapitre 2, l'objectif était de développer un système de délivrance de médicaments capables de pénétrer les lésions cérébrales pour proposer un traitement de la maladie de Parkinson. Pour cela, il a été mis au point la formation d'un nanocomplexe formé d'un dendrimère phosphoré porteur de groupements hydroxyl en surface, combiné avec la fibronectine, qui règle la prolifération et la différenciation et la motilité cellulaire. Sur un modèle murin de la maladie de Parkinson, il a été mis en évidence une pénétration efficace au niveau de la BBB (blood brain barrier) de l'assemblage dendrimère phosphoré AK-123 et fibronectine exerçant une activité anti-inflammatoire et antioxydante permettant de soulager efficacement les symptômes observés et démontrant le grand potentiel pour un traitement clinique de la maladie de Parkinson mais aussi ouvrant un espoir de viser d'autres maladies neurodégénératives. Au Chapitre 3, les résultats obtenus dans le domaine de la maladie de Parkinson lors de l'action conjuguée d'un dendrimère phosphoré de génération 2 comportant 48 groupements hydroxy en surface et de la fibronectine nous ont incités à diversifier la nature et la structure de ces dendrimères afin d'avoir des premières indications de leur activité en général et d'aborder éventuellement une étude SAR (relation structure activité). Pour cela nous avons pu préparer tout un ensemble de nouveaux dendrimères phosphorés neutres de générations 1 et 2, caractérisés par des structures internes différentes de celles des dendrimères utilisés dans le chapitre précèdent, et de longues chaines en surface comportant également des groupements hydroxyle. Ces dendrimères ont l'avantage de posséder des groupements amines protonées permettant une solubilité en milieu aqueux. Nous avons pu également préparer des dendrons phosphorés neutres et chargés. Des résultats préliminaires concernant leurs propriétés ont pu être mis en évidence. Au Chapitre 4, Le but de notre étude a porté tout d'abord sur la synthèse de dendrimères phosphorés anioniques originaux et à l'utilisation d'un de ces dendrimères en l'occurrence le dendrimère AK 137 qui présente une activité anti-inflammatoire optimale et une grande aptitude pour la délivrance de protéines. Des nanocomplexes stables formés par ce dendrimère et diverses protéines en solution aqueuse (bovine serum albumin (BSA), ribonucleaseA (RNaA), ovalbumine (OVA) et fibronectine (FN) ont été obtenus. Nous avons pu démontrer que l'association AK-137@FN NCs bloque l'activation de certaines voies de signalisation (NF-kB et P13K/Akt), induit la polarisation de macrophages vers des phénotypes M2, inhibe la sécrétion de cytokines pro-inflammatoires (TNF-alpha, IL-1beta et IL6) et augmente les propriétés antioxydante de FN in vitro. Les effets thérapeutiques de l'association AK-137@FN ont été démontrés sur des modèles de souris ALI (acute lung injury) et AGA (acute gout arthritis) sans observation de toxicité systémiqueThe objective of this thesis work was to prepare new phosphorous dendrimers or phosphorous dendrons, either neutral, cationic or anionic, with the aim of broadening the range of applications in the field of nanomedicine as molecules active by per se. or in combination with certain medications. In Chapter 1, the synthesis of a new polycationic phosphorus dendrimer comprising 5 pyrrolidinium groups on the surface and a protonated amine was successfully completed. This dendrimer associated with microRNA-30d makes it possible to obtain polyplexes which are transferred into cancer cells in an optimal N/P ratio of 10. These polyplexes are cytocompatible and transfer miR-30d to suppress glycolysis associated with SLC2A1. The inhibition of the migration and invasion of murine cancer cells in vitro and in vivo were thus demonstrated. This dendrimer can be considered as an important component for therapy based on the use of miR-30d. In Chapter 2, we develop a drug delivery system capable of penetrating BBB (blood brain barrier) to provide treatment for degenerative disorders. For this, the formation of a nanocomplex was developed consisting of a phosphorus dendrimer carrying hydroxyl groups on the surface, combined with fibronectin, which regulates proliferation and differentiation and cell motility. In a mouse model of Parkinson's disease, effective penetration at the level of the BBB of the phosphorous dendrimer assembly AK-123 and fibronectin was demonstrated, exerting an anti-inflammatory and antioxidant activity allowing to decrease effectively the symptoms observed and demonstrating the great potential for clinical treatment of Parkinson's disease but also hold great promise to be used to tackle other neurodegenerative disorders. In Chapter 3, the results obtained in the field of Parkinson's disease during the combined action of a generation 2 phosphorous dendrimer comprising 48 hydroxyl groups on the surface and fibronectin have encouraged us to diversify the nature and structure of these dendrimers in order to have first indications of their activity in general and to possibly approach a SAR (structure activity relationship) study. According to these, we prepared a whole set of new neutral phosphorus dendrimers of generations 1 and 2, characterized by internal structures different from those of the dendrimers used in the previous chapter, incorporating long chains on the surface and also comprising hydroxyl groups. These dendrimers have the advantage of having protonated amine groups allowing solubility in an aqueous medium. We were also able to prepare neutral and charged phosphorous dendrons. Preliminary results concerning their properties have been demonstrated. In Chapter 4, the aim of this study was focused on the synthesis of original anionic phosphorus dendrimers and the application of these dendrimers, and particularly of the dendrimer AK 137 which presents optimal anti-inflammatory activity and great efficiency for the delivery of proteins. We demonstrate that the AK-137@FN NCs association blocks the activation of certain signalling pathways (NF-kB and P13K/Akt), induces the polarization of macrophages towards M2 phenotypes, inhibits the secretion of pro-cytokines. (TNF-alpha, IL-1beta and IL6) and increases the antioxidant properties of FN in vitro. The therapeutic effects of the AK-137@FN combination have been demonstrated in ALI (acute lung injury) and AGA (acute gout arthritis) mouse models without observation of systemic toxicity
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Dussart, Jade. "Phosphinates : des développements méthodologiques aux applications biomédicales." Thesis, Paris 13, 2019. http://www.theses.fr/2019PA131067.
Повний текст джерелаАнотація:
Les H-phosphinates représentent des pharmacophores intéressants en chimie médicinale et nécessitent le développement de méthodologies reproductibles pour la conception de composés d’intérêt. C’est pourquoi une étude méthodologique a été proposée pour la réaction d’Abramov en vue de la synthèse d’hydroxyphosphinates. Cette méthode a également pu être appliquée sur des dérivés trivalents tels que les chlorures d’acide, les anhydrides d’acide et les esters activés pour la formation de 1-hydroxyméthylène-1,1-bisphosphinates et de phosphino-phosphonates. La compréhension de chaque réaction s’est appuyée sur une étude approfondie de suivi en RMN du phosphore, ce qui a permis l’identification des différents intermédiaires de synthèse et la compréhension du mécanisme réactionnel. La méthode a ainsi pu être appliquée sur des substrats fonctionnalisés pour des applications biomédicales telles que l’évaluation de l’activité inhibitrice de ces molécules sur une lignée cancéreuse ainsi que l’élaboration de nanoparticules d’or qui permettront de vectoriser ces composés. Ces nanovecteurs seront également évalués biologiquement à terme sur des lignées cancéreusesH-phosphinates represent an interesting scaffold in medicinal chemistry and require the development of reproducible methodologies for the conception of bioactive compounds. This is why a methodological study has been proposed for the Abramov reaction for the synthesis of hydroxyphosphinates. This method could also be applied to trivalent derivatives such as acid chlorides, acid anhydrides and activated esters for the formation of 1-hydroxymethylene-1,1-bisphosphinates and phosphino-phosphonates. The understanding of each reaction was based on a detailed phosphorus NMR monitoring study which allowed the identification of the different synthetic intermediates and the understanding of the reaction mechanism. Thereafter, the method has been applied to functionalised substrates for biomedical applications such as their inhibitory activity evaluation on a cancer cell line. These compounds also permit to synthesise new gold nanovectors in order to evaluate their biologically activities on cancerous cell lines
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Aimard, Adrien. "Ciblage de la protéine peroxysomale PMP34/SLC25A17 par des composés de type thiomorpholine hydroxamate dans le cancer." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0765.
Повний текст джерелаАнотація:
Le repositionnement des médicaments est une stratégie visant à trouver de nouvelles indications pour des médicaments existants. Un composé de type thiomorpholine hydroxamate (TMI-1, un inhibiteur d'ADAM-17 utilisé dans le traitement des maladies chroniques inflammatoires) a récemment été repositionné dans le traitement du cancer. Afin d’élucider son mécanisme d'action, une série de dérivés de type d'arysulfonyl thiomorpholine hydroxamate a été synthétisée et évaluée pour déterminer une relation entre structure et activité . Nous avons démontré que l'activité cytotoxique observée dépend du fragment phényl hydroxamate et n'est pas liée à l'inhibition de l'ADAM-17. Grâce à une approche par protéomique inverse, nous avons identifié la protéine membranaire peroxysomale PMP34 / SLC25A17 comme une nouvelle cible de TMI-1. PMP34 est un transporteur transmembranaire de différents cofacteurs nécessaires à la fonction des peroxysomes. Nous démontrons ici que TMI-1 se lie directement à PMP34 et augmente l’interaction entre PMP34 et PEX19, une protéine chaperone impliquée dans l’assemblage et la biologie des peroxysomes, alors que les expériences sur les ARNi ont révélé que PMP34 est essentielle à la viabilité des cellules tumorales. Enfin, le traitement des cellules tumorales par TMI-1 induit une modification de la composition en protéines du peroxysome et augmente le niveau de la protéine PMP70 / ABCD3. Un taux élevé de PMP70 dans le peroxysome augmente la $\beta$-oxydation des acides gras ce qui pourrait entraîner la mort des cellules cancéreuses. En conséquence, PMP34 représente une nouvelle cible intéressante en oncologieDrug repositioning is a strategy to find new indications for existing drugs. A thiomorpholine hydroxamate compound (TMI-1, an ADAM-17 inhibitor used for the treatment of chronic inflammatory diseases) has been recently repositioned in cancer. To further elucidate its mechanism of action, a series of arylsulfonyl thiomorpholine hydroxamate derivatives was synthetized and evaluated to determine a structure-activity relationship. We have pinpointed that the observed cytotoxic activity depends on the hydroxamate phenyl moiety and is not related to ADAM-17 inhibition. Using a reverse proteomic approach, we now identify the peroxisomal membrane protein PMP34/SLC25A17 as a new target of TMI-1. PMP34 is a transmembrane transporter of different cofactors required for peroxisome function. We demonstrate here that TMI-1 directly binds to PMP34 and increases the interaction between PMP34 and PEX19, a chaperone protein involved in peroxisome assembly and biology while RNAi experiments revealed that PMP34 is essential for tumor cell viability. Finally, TMI-1 treatment of tumor cells induces modification of peroxisome protein composition and increases the level PMP70/ABCD3 protein. High PMP70 level in peroxisome increases fatty acid $\beta$-oxidation that could lead to cancer cell death. As a result, PMP34 represents a new valuable target in oncology
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Delgado, Soler Laura. "Optimització in silico de compostos antitumorals." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/32013.
Повний текст джерелаАнотація:
La medicina personalitzada i les teràpies dirigides són, avui dia, estratègies emergents en les companyies farmacèutiques. L’objectiu global, a llarg termini, és desenvolupar tractaments dirigits cap a mecanismes moleculars desregulats únicament en les cèl•lules afectades, reduint així els problemes de toxicitat d’aquests compostos. Aquest procés és llarg i costós però la introducció de les tècniques de disseny racional de fàrmacs ha permès reduir de manera considerable el temps d’identificació de molècules actives, agilitzant així les etapes inicials.
Les teràpies antitumorals dirigides a promoure l’apoptosi i/o a controlar el procés de proliferació cel•lular es troben avui dia en ple desenvolupament. A més, les oportunitats d’intervenció terapèutiques en aquesta línia s’incrementen a mesura que augmenta el coneixement de les proteïnes involucrades en aquests processos. Avui dia els principals problemes dels compostos identificats radiquen però en la seva selectivitat i el gran nombre d’efectes secundaris que presenten, pel que el disseny del molècules selectives és un camp de recerca molt actiu.
El present projecte es basa en la cerca de nous fàrmacs anticancerígens mitjançant la modelització molecular. D’una banda es tracta d’identificar inhibidors per a les proteïnes de la família Bcl-2 per a restablir els nivells normals d’apoptosi i, de l’altra, per a les proteïnes CDK4 i CDK6, importants reguladores del cicle cel•lular. L’objectiu plantejat a llarg termini en aquesta tesi és identificar compostos actius amb potència i selectivitat cap a aquestes proteïnes per tal de convertir-los en caps de sèrie que finalment puguin arribar a ser fàrmacs comercials.
La utilització de compostos mimètics del domini BH3 per inhibir la funció dels membres antiapoptòtics de la família Bcl-2 és una de les estratègies més emprades per al control de l’apoptosi. En aquest marc, en funció de la selectivitat que presenten envers els pèptids BH3, podem trobar dues subfamílies de proteïnes antiapoptòtiques: Bcl-2, Bcl-xL i Bcl-w d’una banda i Mcl-1 i A-1 de l’altra. Diferents estudis suggereixen que per a produir la mort cel•lular és necessari intervenir al menys un membre de cadascuna de les subfamílies. Per tant, sota aquesta premissa, es van analitzar les interaccions establertes entre les proteïnes antiapoptòtiques i dominis BH3 tant pel cas de pèptids que s’uneixen amb igual afinitat a tota la família, com per a pèptids selectius de cadascun dels subgrups.
Nombrosos estudis apunten a que la helicitat en els pèptids mimètics dels domini BH3 incrementa notablement l’afinitat d’enllaç. Sota aquesta premissa s’ha tractat de dissenyar pèptids derivats de la proteïna proapoptòtica Bak substituint alguns dels residus prescindibles per l’aminoàcid no natural Aib, inductor de conformacions helicoïdals.
Actualment tots els inhibidors coneguts per a les CDKs, actuen sobre el lloc d’unió de l’ATP. Donat que existeix una gran quantitat de dades experimentals sobre aquests compostos es va decidir avaluar diferents algoritmes de docking i predicció d’afinitats experimentals amb cinc inhibidors coneguts de CDK6.
Finalment, s’ha proposat també un desenvolupament metodològic que enfoca el problema del disseny de fàrmacs des d’una perspectiva més amplia: la quimiogenòmica. Amb la seqüenciació del genoma humà s’ha pres consciència de que resulta inviable avaluar el gran número de compostos químics coneguts actualment sobre totes les possibles dianes terapèutiques identificades en el genoma humà. Per aquest motiu és imprescindible desenvolupar mètodes teòrics més senzills per a la caracterització i comparació de molècules que permetin predir la seva activitat biològica.
Així doncs, amb la realització d’aquesta tesi, queda patent que l’aplicació de mètodes teòrics pot contribuir de manera eficient al disseny de fàrmacs. D’aquesta manera es possible reduir el cost i temps necessari per al descobriment de compostos actius.Nowadays, personalized medicine and directed therapies have emerged as appealing strategies for pharmaceutical companies. The long-term goal is developing new treatments to target molecular pathways altered only in affected cells, thus reducing undesired side effects and toxicity problems. This is a tedious and long process although the incorporation in its framework of rational drug design techniques has reduced the time needed to identify new active molecules. The knowledge of molecular mechanisms involved in a given pathology allows finding a point of the process that can be targeted, usually a protein, restoring the normal cell behavior. Once identified the therapeutic target it is possible to find compounds that reproduce interactions between this protein and the corresponding natural regulations by means of molecular modeling techniques. In principle, these compounds are expected to mimic the biological effect of the natural regulators. Antitumoral therapies oriented to promote apopotosis or control the cell proliferation process are gaining importance nowadays. In addition, opportunities for therapeutic intervention in this context are growing with the discovery of new proteins involved in these pathways. In fact, the drawback of compounds known at date relies on selectivity problems and, thus, the huge number of undesired side effects of these treatments. Hence, development of selective treatments is a very active research field. The goal of the present PhD project is to identify new anticancer agents using molecular modeling techniques. On the one hand, it has been tried to identify inhibitors of the Bcl-2 protein family in order to restore normal apoptosis levels in tumoral cells and, on the other hand, for the CDK4 and CDK6 proteins, key regulators of eukaryotic cell cycle. All these proteins are deregulated in many types of cancer and thus, are presented as interesting targets for the cancer treatment. The identification of compounds with potency and selectivity for these proteins that can be used as lead compounds that finally will become commercial drugs is seeked.
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Defaux, Julien. "Synthèse et évaluation pharmacologique de composés azahétérocycliques à visée antitumorale." Nantes, 2009. https://archive.bu.univ-nantes.fr/pollux/show/show?id=4c8b5ca7-21e9-4520-b2ce-0713577ea5df.
Повний текст джерелаАнотація:
Malgré la découverte de nouvelles molécules antitumorales et l'application de nouveaux traitements, le cancer reste une des principales causes de décès dans les pays développés. Des travaux antérieurs ont montré que des composés à structure pyrido[2,3-b ]pyrazine possédaient un niveau d'activité prometteur sur la cascade des MAP kinases impliquée dans la prolifération de nombreux cancers. Nous avons décidé, en collaboration avec les laboratoires AEterna Zentaris, de développer des molécules originales, à structure 1,5- naphtyridine, dérivées des composés précédemment cités. Dans un premier temps, une synthèse efficace a donc été mise au point, puis dans un deuxième temps, une pharmacomodulation couplée à des évaluations pharmacologiques nous ont permis d'obtenir de nouveaux inhibiteurs de kinasesDespite the discovery of novel antitumor agents and the application of new therapies, cancer disease is one of the most important cause of death in developed countries. Previous works demonstrated that pyrido[2,3-b [pyrazine derivatives exhibited a promising activity on MAP kinases cascade which is involved in tumor proliferation. Thus, we decided, in collaboration with AEterna Zentaris laboratories, to develop new 1,5-naphthyridine compounds derived from the previous ones. First, we perfected an efficient synthesis, then we made pharmacomodulation and pharmacological evaluations to obtain new kinases inhibitors
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HUI, XIAOWEN. "Etude theorique des interactions entre les acides nucleiques et les composes antitumoraux." Paris 6, 1992. http://www.theses.fr/1992PA066512.
Повний текст джерелаАнотація:
L'adn est une cible privilegiee des molecules antitumorales, et trois modes distincts d'interaction en ont ete degages: intercalation, interaction nonintercalante, ou fixation covalente. A l'aide de methodologies theoriques developpees exclusivement au laboratoire, et pour des familles bien ciblees de complexes, nous tenterons de faire ressortir de maniere quantitative cette double composante, energetique et structurale, qui constitue le fondement de la reconnaissance moleculaire. Nos calculs theoriques ont permis de faire ressortir les aspects structuraux et energetiques les plus notables de ces complexes et la tres grande diversite des modes d'association respectifs. La distamycine, molecule monocationique, se lie dans le petit sillon, avec une preference pour les sequences at. L'olivomycine, constitue un exemple rare de molecules nonintercalantes complexant preferentiellement les sequences gc de l'adn dans le petit sillon. Une molecule dicationique, le dipyrandium, a une preference marquee pour les sequences at, et pour le petit sillon, avec une deformation importante de l'adn. Une autre molecule tetracationique, la t4mpyp, presente la caracteristique remarquable de s'associer a l'adn dans deux configurations bien distinctes: intercalation avec les sequences gc, et fixation dans le petit sillon avec les sequences at. La mitoxantrone, une des tres rares molecules intercalantes dont les chaines laterales complexent toutes deux le grand sillon de l'adn. Un derive bis-monopeptidique de cette molecule, interagit avec l'adn en disposant chaque bras dans un sillon different
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Nasr, El Dine Assaad. "Développement de nouvelles méthodes de synthèse en chimie de fluor et préparation de molécules bioactives." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1S158/document.
Повний текст джерелаАнотація:
Ce travail s'inscrit dans le cadre d'un programme de collaboration entre l'Université Libanaise et l'université de Rennes 1. La thèse est divisée en deux parties :Chimie du fluor : synthèse de nouveaux hétérocycles portant des chaînes latérales fluorées ; chimie médicinale : recherche de nouvelles molécules à visées anticancéreuses. La première partie se compose de trois chapitres : dans le premier chapitre, des intermédiaires de synthèse de type énones fluorées ont été synthétisés par une voie originale, et leur réactivité en cyclocondensation a été étudiée pour obtenir de pyrazolines et de pyrrolines avec des chaînes latérales fluorés. Dans le deuxième chapitre, nous nous sommes intéressés à la préparation d'hétérocycles de type chroman-4-one, en utilisant les intermédiaires difluorés précédents. Dans le dernier chapitre, la réaction de Kinugasa a été appliquée pour la première fois sur des dérivés propargyliques gem-difluorés. Cette réaction nous a permis de découvrir une voie de synthèse originale à une famille de composés nouveaux, à savoir des exoalkylidène b-lactames portant un fluor en position vinylique. Dans la seconde partie, notre objectif était de restaurer les propriétés apoptotiques au sein des cellules cancéreuses afin d'obtenir de nouveaux composés à activité antitumorale. A partir de données obtenues par modélisation moléculaire, nous avons fait le design de plusieurs séries d'analogues d'un inhibiteur connu (MIM-1) de la protéine anti-apoptotique Mcl-1. Plus de 40 analogues ont été préparés et testés sur trois variétés de cellules cancéreuses (sein, ovaire et mélanome). Un certain nombre de ces composés ont présenté des activités prometteuses dans ces différents domainesThis work is a part of a collaboration program between Lebanese University and University of Rennes 1. The thesis is divided into two parts: fluorine chemistryv : synthesis of new heterocycles bearing fluorine-containing side chains ; medicinal chemistry : research towards new anticancer molecules. The first part consists of three chapters: in the first chapter, gem-difluoro enone-type intermediates were synthesized through a new route and their cyclocondensation reactions were studied to get pyrazolines and pyrrolines with fluorinated side chains. In the second chapter, type-chroman-4-one heterocycles were prepared using the previous difluorinated intermediates. In the third chapter, the Kinugasa reaction was applied for the first time on gem-difluoro propargylic derivatives. This reaction has allowed us to discover a pathway to a new family of molecules, the fluorine-containing exoalkylidene β-lactames. In the second part, our goal was to reinduce the proapoptotic properties in cancer cells in order to obtain new antitumor compounds. Starting from data obtained through molecular modeling studies, we designed and prepared several series of analogs for a known inhibitor (MIM-1) of the anti-apoptotic protein Mcl-1. Over 40 analogs have been synthetized and screened towards three types of cancer cells (breast, ovarian and melanoma). Some of these derivatives have demonstrated promising data in these areas
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Bourderioux, Aurélie. "Synthèse d'hybrides d'indolocarbazoles et de la caulersine, composés à visée antitumorale." Phd thesis, Université d'Orléans, 2007. http://tel.archives-ouvertes.fr/tel-00147916.
Повний текст джерелаАнотація:
Le cancer, qui est la deuxième cause de mortalité en France, est aujourd'hui un problème de santé publique majeur et fait l'objet de multiples recherches. De nombreuses molécules ont été synthétisées dans l'optique de trouver des médicaments plus efficaces, plus sélectifs et surtout présentant moins d'effets secondaires. Parmi ces molécules se trouve la famille des indolocarbazoles, dont la rébeccamycine et la staurosporine sont les représentants les plus connus. Les relations structure-activité (RSA) de cette famille ont été étudiées.Dans le cadre de la recherche de nouveaux agents cytotoxiques et d'inhibiteurs de kinases toujours plus sélectifs, la structure principale des phénylcarbazoles, appartenant à la famille des indolocarbazoles, a été modifiée par introduction d'une tropone centrale, cycle à 7 chaînons porteur d'une fonction carbonyle. Les différentes voies de synthèse permettant d'accéder à cette nouvelle famille de composés appelés oxophénylarcyriaflavines ont été étudiées. La méthode de choix retenue pour l'étape finale de la synthèse est la cyclisation électrophile en position 2 de l'indole. Cette synthèse a ensuite été généralisée aux composés substitués par des groupements hydroxyles en position 5 de l'indole d'une part et en position 4' et 5' du noyau phényle d'autre part. Les 17 molécules finales ainsi synthétisées ont subi divers tests biologiques permettant d'établir les RSA de cette nouvelle famille de composés. Finalement, la méthodologie mise au point pour les oxophénylarcyriaflavines a été étendue à la synthèse de la toute première famille de composés bisindoliques possédant également une tropone centrale.
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Antoine, Maud. "Synthèse et évaluation pharmacologique de composés indoliques et pyridopyraziniques à visée antitumorale." Nantes, 2005. https://archive.bu.univ-nantes.fr/pollux/show/show?id=f2c53739-f770-45cf-8fd6-82535e3514ee.
Повний текст джерелаАнотація:
Des travaux préalablement réalisés dans notre laboratoire ont montré l’intérêt thérapeutique en chimiothérapie anticancéreuse du 2-[1-(4-chlorobenzyl)indol-3-yl]-N-(pyridin-4-yl)glyoxamide I en tant qu’inhibiteur de la polymérisation de la tubuline. Tout en conservant la structure de base de I, l’accès à des analogues en position 4 et 5 du noyau indolique, ainsi que la pharmacomodulation sur le groupement 4-chlorobenzyle et en position 3 de l’hétérocycle en séries acide aminé, vinylogue et 2,4-dioxobutyramide sont décrits. Les protéines kinases constituent une cible thérapeutique d’intérêt croissant, notamment dans le traitement des cancers. La conception de pyrido[2,3-b] et [3,4-b]pyrazines substituées en position 2, 3 et 8, inhibiteurs potentiels de kinases, est développée. L’accès à ces structures a été envisagé par condensation entre une orthodiaminopyridine et une dicétone symétrique en série biaryle. Diverses voies d’accès en série monoaryle sont également décritesPrevious works in our laboratory showed the therapeutic interest for antitumor chemotherapy of 2-[1-(4-chlorobenzyl)indol-3-yl]-N-(pyridin-4-yl)glyoxamide I as a tubuline polymerisation inhibitor. Keeping the core structure of I, the access to the analogues in positions 4 and 5 of the indole ring and the pharmacomodulation of the 4-chlorobenzyle moiety and in position 3 of the heterocycle in amino-acid, vinylogue and 2,4-dioxobutyramide series are described. Protein kinases constitute a therapeutic target with growing interest, especially in cancer treatment. The conception of pyrido[2,3-b] or [3,4-b]pyrazines substituted in positions 2,3 or 8, potent kinase inhibitors, is developed. The access to these structures was envisaged by the condensation between an orthodiaminopyridine and a symmetrical diketone in biaryl series. Various routes in monoaryles are also described
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Carvalho, Marcos Alberto de 1983. "Síntese e caracterização estrutural de complexos metálicos com ligantes bioativos N,O-doadores e estudo de suas atividades biológicas in vitro." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249130.
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Orientadores: Pedro Paulo Corbi, André Luiz Barboza FormigaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: O uso de metais em medicina, no tratamento de doenças, data desde a antiguidade. Sais de prata são utilizados há séculos como agentes antimicrobianos, enquanto que, mais recentemente, complexos de Au(I) e Pt(II) tem sido pesquisados e utilizados como agentes antiartríticos e antitumorais, respectivamente. Nesta Tese, são apresentados estudos de síntese, caracterização estrutural e ensaios biológicos in vitro de novos complexos metálicos de Pt(II), Pd(II), Ag(I) e Au(III) com diferentes ligantes bioativos: triptofano (Trp), triptamina (tra), ácido mefenâmico (mef) e carnosina (car). Os complexos foram preparados a partir da reação em solução aquosa ou alcoólica dos ligantes e dos respectivos sais metálicos. As composições dos complexos foram determinadas por análise elementar, espectrometria de massas e por análise termogravimétrica. Estudos espectroscópicos e de modelagem molecular permitiram propor os modos de coordenação dos ligantes aos íons metálicos. Os complexos de Ag(I) e Pd(II) com Trp mostraram atividade sobre cepas bacterianas Gram-negativas e Gram-positivas. O complexo de Pd(II) com triptamina não apresentou atividade frente as cepas de Escherichia coli, Pseudomonas aeruginosa e Staphylococcus aureus. O complexo de Pd(II) com ácido mefenâmico e bipiridina mostrou atividade inibitória frente a cepas de S. aureus e não foi ativo sobre E. coli e P. aeruginosa. Estudos de citotoxicidade dos complexos de Ag(I), Pd(II) e Pt(II) com Trp pela redução do MTT sobre as linhagens de células Balb/c3T3, SK-Mel 103 e Panc-1 mostraram que os complexos são citotóxicos para todas as linhagens consideradas
Abstract: The use of metals in medicine in the treatment of diseases dates since antiquity. Silver salts have been used as antimicrobial agents for centuries, while more recently, Au(I) and Pt(II) complexes have been investigated and used as antiarthritic and antitumor agents, respectively. This Thesis presents the synthesis, structural characterization and biological assays in vitro of new metal complexes of Ag(I), Pd(II), Pt(II) and Au(III) with the bioactive ligands tryptophan (Trp), tryptamine (tra), mefenamic acid (mef) and carnosine (car). The complexes were prepared by the reaction of the ligands and metal salts in aqueous or alcoholic solutions. Composition of complexes were determined by elemental analysis, mass spectrometry and thermogravimetric analyses. Spectroscopic and molecular modeling studies were used to determine the coordination modes of the ligands to the metals. Complexes of Ag(I) and Pd(II) with Trp showed activity against Gram-positive and Gram-negative strains. The Pd(II) complex with tryptamine showed no activity against Escherichia coli, Pseudomonas aeruginosa ande Staphylococcus aureus strains. The Pd(II) complex with mefenamic acid and bipyridine showed inhibitory activity against S. aureus strains and it was not active on E. coli and P. aeruginosa. Cytotoxicity studies of the Ag(I), Pd(II) and Pt(II) complexes with Trp by MTT reduction on Balb/c3T3, SK-Mel 103 and Panc-1 lines cells showed that complexes are cytotoxic to all considered cells
Doutorado
Quimica Inorganica
Doutor em Ciências
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Serrano, Fabiana do Amaral [UNIFESP]. "Novos compostos de paládio e rutênio com atividade antitumoral." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9844.
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Previous issue date: 2009-11-25O melanoma é a forma mais agressiva de câncer de pele em virtude do elevado grau de proliferação, invasão e metástase das células tumorais. Menos de 10% dos pacientes com melanoma metastático sobrevivem por 5 anos. Quimioterapias com um único composto são bem toleradas, mas associadas a baixas taxas de resposta terapêutica. Associações de quimioterápicos já aprovados para uso humano também foram relacionadas a baixas taxas de resposta, sem redução da toxicidade. Logo, a identificação de novos agentes antitumorais é crítica para o tratamento do melanoma, e este trabalho buscou avaliar a atividade antitumoral de novos quimioterápicos derivados de paládio e rutênio no modelo pré-clínico de melanoma murino B16F10-Nex2. Um composto ciclopaladado, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], denominado C7A, avaliado anteriormente pelo nosso grupo, demonstrou elevada atividade antitumoral e baixa toxicidade in vivo, porém, seu mecanismo de ação ainda não estava determinado. Neste trabalho demonstramos que este composto interage com grupos tiol presentes em proteínas da membrana mitocondrial, induzindo uma abrupta redução na acidificação extracelular, colapso do potencial de membrana mitocondrial e translocação da proteína Bax para o interior dessa organela. Evidenciamos também um aumento nas concentrações intracelulares de cálcio, proveniente de organelas celulares e do meio extracelular. Estes efeitos iniciais causaram ativação de caspases efetoras, condensação nuclear, degradação do DNA e dramáticas alterações morfológicas nessas células. Esses dados sugerem que C7A provoca uma morte celular por apoptose induzindo a via intrínseca em células de melanoma murino B16F10-Nex2. Observou-se que células tumorais humanas são sensíveis ao C7A, e o mecanismo de ação do composto nessas células parece ser idêntico ao observado em células murinas. O ciclopaladado 7A reduziu significativamente o número de nódulos pulmonares sem toxicidade aparente, indicando sua eficiência também contra tumores metastáticos. A atividade antitumoral de diversos compostos nitrosil-tetraamina-rutênio (trans-[RuII(NH3)4(L)NO+], onde L corresponde a diferentes ligantes de estabilização, e que são doadores de óxido nítrico (NO) em meios biológicos foi avaliada. Todos os compostos testados foram citotóxicos in vitro para células tumorais murinas e humanas. Alguns compostos foram selecionados e avaliados in vivo, mostrando uma elevada toxicidade em paralelo a uma atividade antitumoral. No entanto, observou-se que os compostos onde o NO havia sido substituído por um radical sulfato, utilizados como controles dos compostos doadores de NO, apresentaram elevada atividade antitumoral e baixa toxicidade in vivo, retardando o desenvolvimento do tumor subcutâneo e prolongando a sobrevida dos animais tratados. Os compostos sulfatados também apresentaram baixa toxicidade ao reduzir o número de nódulos metastáticos dos animais tratados. Esses compostos também foram citotóxicos in vitro para células tumorais humanas, e as alterações morfológicas, externalização de fosfatidilserina, condensação nuclear e degradação de DNA observados sugerem que os compostos tetraamina rutênio sulfatados levam a célula tumoral à morte por apoptose. Ambos os quimioterápicos testados abrem novas possibilidades para o tratamento do melanoma maligno.
Melanoma is the most aggressive form of skin cancer mainly because of the high degree of tumor cell proliferation, invasion and metastasis. Less than 10% of metastatic melanoma patients show 5 years survival. Single drug chemotherapy is well tolerated but associated with low response rates. Associations of chemotherapeutic agents approved for human use are related to low response rates, without improvement on side effects. Therefore, the identification of new antitumor agents is critical to melanoma treatment, and this study aimed to evaluate the antitumor effect of novel palladium and rutheniun derived chemotherapeutic drugs in the preclinical model of murine melanoma B16F10-Nex2. A cyclopalladated compound, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], named C7A was previously evaluated by our group. The complex showed high antitumor and low toxicity in vivo, however, the targets for this compound in tumor cells were not determined yet. In this work we demonstrated that C7A interacts with thiol proteins present in the mitochondrial membrane, leading to an abrupt reduction of extracellular acidification, collapse of mitochondrial membrane potential and Bax translocation to the interior of this organelle. It was also observed an increase in intracellular calcium concentrations, originated from cellular organelles as well as from extracellular medium. These initial effects caused activation of effector caspases, nuclear condensation, DNA degradation and dramatic morphological changes in these cells. All these data suggests that the cyclopalladated 7A induces the intrinsic pathway apoptotic cell death on B16F10-Nex2 murine melanoma cells. Human tumor cells are sensitive to this compound and mitochondria also seem to be the target for C7A on these cells. Cyclopalladated 7A significantly reduced the number of pulmonary nodules with no apparent toxicity, indicating that this compound is also active against metastatic melanoma lesions. Antitumor activity of several nitrosyl tetraammine ruthenium compounds with general formula (trans-[RuII(NH3)4(L)NO+], where L corresponds to different stabilization ligands, were evaluated. These compounds are nitric oxide (NO) donors in biological media. All tested compounds were cytotoxic in vitro to human and murine tumor cells. Some compounds were selected and evaluated in vivo, showing numerous side effects in association with the antitumor effect. However, it was found that the compounds where the NO was replaced by a sulfate group, used regularly as a negative control for NO-donor ruthenium complexes, showed a pronounced antitumor activity and low toxicity in vivo, delaying subcutaneous tumor development and extending survival of treated animals. Sulfate compounds also reduced the number of metastatic lung nodules with no apparent toxicity. These compounds were also cytotoxic for human tumor cells in vitro, and the morphological alterations, phosphatidylserine externalization, nuclear condensation and DNA degradation observed after cell treatment suggested that sulfate tetraamine compounds induced an apoptotic cell death. Both evaluated chemotherapeutic drugs open new possibilities for malignant melanoma treatment.
TEDE
BV UNIFESP: Teses e dissertações
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Boualam, Mohammed. "Carboxylates aromatiques de diorganoetains et composés analogues.Synthèse, étude structurale et activité antitumorale in vitro." Doctoral thesis, Universite Libre de Bruxelles, 1991. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/213033.
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Buon, Christophe. "Synthese et activite antitumorale de composes polycycliques a structure benzodioxinique ou benzoxazinique." Orléans, 1999. http://www.theses.fr/1999ORLE2005.
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Chaque annee, dans le monde entier, un nombre croissant de personnes sont victimes du cancer. La chimiotherapie, utilisee seule ou en complement, reste l'un des traitements les plus employes avec la chirurgie, la radiotherapie, l'endocrinotherapie et l'immunotherapie. Dans le cadre de la recherche de nouveaux agents anticancereux, nous avons prepares des composes polycycliques comportant une sous-structure benzodioxinique ou benzoxazinique. Il s'agit de systemes tetra ou pentacycliques, plans, porteurs d'une chaine aminee protonable susceptible d'augmenter leur affinite pour les cibles biologiques. Pour acceder a ces derives, nous nous sommes particulierement interesses a la preparation et a la fonctionnalisation des 4h-1,4-benzoxazines. Les strategies mises en oeuvre font appel a des reactions anioniques et a des reactions de couplage catalysees par des metaux de transition, notamment le couplage d'un phosphate vinylique de la benzoxazine et de divers organostannanes en presence de palladium (0). Plusieurs voies de synthese distinctes ont ete mises au point pour acceder aux molecules polycycliques recherchees ; elles font appel pour l'essentiel a des cycloadditions de diels-alder et a des cyclisations intramoleculaires. Ces etudes ont egalement permis d'acceder a des diarylamines qui constituent des precureurs particulierement adaptes a la synthese de benzoxazolones-n-aryles et de 11h-benzoacarbazoles. Les tests pharmacologiques in vitro, realises sur les benzoaphenoxazines, sont particulierement encourageants aussi bien en terme de cytotoxicite que de perturbation du cycle cellulaire.
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Perez, Marc. "Conception, hémisynthèse et évaluation biologique de composés à visée antitumorale à partir de produits naturels." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066760.
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Ce manuscrit présente l’hémisynthèse de composés à visée antitumorale à partir d’un alcaloïde issu de la plante Securinega suffruticosa, la sécurinine. Des dérivés ont été synthétisés par fragmentation et extension du squelette de la sécurinine. Des réactions d’addition 1,6 ont également été optimisées afin d’accéder à d’autres analogues. Les réactions palladocatalysées de type Heck, Sonogashira et Suzuki ont été employées dans la synthèse de nouveaux dérivés de la sécurinine substitués en position C14 et C15. La cytotoxicité des composés synthétisés a été évaluée sur quatre lignées de cellules cancéreuses et a permis de dresser la relation structure-activité de la sécurinine. En particulier, des dérivés hautement cytotoxiques présentant des IC50 de 60 nM sur la lignée de cellules cancéreuses de peau A375 ont été obtenusThis manuscript reports the semisynthesis of anticancer compounds starting from securinine, an alkaloid found in the shrub Securinega suffruticosa. A set of compounds was obtained by cleavage and functionnalization of the scaffold of securinine. 1,6-addition reaction have been developed to afford further analogues. Palladium-catalyzed cross coupling reactions such as Heck, Sonogashira and Suzuki couplings have been used for the synthesis of new C14 or C15 substituted securinine derivatives. The anticancer properties of these derivatives were assayed against four cancer cell lines and were used to define the structure-activity relationship of securinine. Noteworthy, potent cytotoxic derivatives displaying an IC50 of 60 nM have been obtained
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Galuppo, Larissa Favaretto. "Efeitos antitumorais e hematológicos in vivo do composto mesoiônico sidnona 1." reponame:Repositório Institucional da UFPR, 2015. http://hdl.handle.net/1884/37891.
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Orientadora : Profª. Drª. Alexandra AccoDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 26/03/2015
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Resumo: A incidência do câncer vem aumentando drasticamente, no mundo todo. O principal tratamento para este tipo de enfermidade é a quimioterapia, porém a citotoxicidade dos agentes quimioterápicos é muito alta, o que acaba gerando vários efeitos colaterais para o paciente em tratamento. Tendo em vista as limitações da quimioterapia e o aumento da incidência dessa doença, ressalta-se a importância do estudo de novas substâncias com ação antineoplásica, porém menos citotóxicas e com menos efeitos colaterais, proporcionando uma melhor qualidade de vida ao paciente. O objetivo deste trabalho foi determinar a atividade antitumoral do composto mesoiônico Sidnona 1 (Syd-1) no modelo tumor Walker-256 em ratos, avaliando o crescimento tumoral e o seu possível mecanismo de indução de morte celular (apoptose, estresse oxidativo e participação em vias de inflamação). Para isto foram utilizados ratos Wistar, machos, com peso variando de 180 g a 220 g. Para a indução do tumor foram utilizadas células neoplásicas da linhagem Walker-256, que foram inoculadas por via subcutânea em uma concentração de 1x107 células, no membro pélvico direito dos animais. No dia seguinte à inoculação iniciou-se o tratamento por via oral (gavagem), com o composto Syd-1 na dose de 75 mgokg-1 ou com veículo (Tween 20% e salina) para os grupos: 1) Basal (animais saudáveis, que receberam apenas veículo), 2) Basal-Syd (animais saudáveis, que receberam tratamento com Syd-1), 3) Tumor (animais com tumor, que receberam veículo) e 4) Tumor-Syd (animais com tumor, que receberam tratamento com Syd-1). Após 12 dias de tratamento os animais foram anestesiados para coleta de sangue, em seguida foi realizada a eutanásia para coleta dos demais tecidos. Fígado, tumor, baço e o plasma foram recolhidos e congelados para análises posteriores. Além disso, o volume e peso tumoral foram avaliados. O composto promoveu uma significativa supressão tumoral nos animais do grupo Tumor-Syd, quando comparados com o grupo Tumor. Além disso, houve uma diminuição dos níveis de GSH no tecido tumoral do grupo que recebeu o tratamento com Syd-1, indicando uma possível ação pró-oxidante no tumor, o que pode ser um mecanismo importante para auxiliar no combate à progressão tumoral. As análises bioquímicas demonstraram que o tratamento com a Syd-1 tende a amenizar alguns danos causados pela síndrome da caquexia. Não foi observada ação anti-inflamatória pelo tratamento com o composto. Ao se investigar as vias apoptóticas observou-se que no grupo Tumor-Syd houve um aumento da expressão das proteínas pró-apoptóticas Bax e p53 e diminuição da anti-apoptótica Bcl-2, indicando que o mecanismo de ação da Syd-1 ocorre pela modulação da apoptose. Nos animais tradados com Syd-1 (grupos Basal-Syd e Tumor-Syd) também houve uma considerável esplenomegalia quando comparados aos demais grupos, o que explica as alterações hematológicas observadas, como aumento de VCM, HCM e RDW. Análises histológicas demonstraram presença considerável de ferro no baço dos animais tratados com Syd-1, levando à hipótese de que a esplenomegalia ocorre por uma extensa hemólise induzida pelo composto. Em conclusão, foi demonstrada a significativa ação antitumoral do composto Syd-1 frente ao modelo de carcinossarcoma Walker-256, através de mecanismos que envolvem ativação de vias apoptóticas, porém os seus efeitos colaterais, como os hematológicos e a esplenomegalia, devem ser melhor elucidados. Palavras-chave: Câncer, Walker-256, Syd-1, Apoptose, Esplenomegalia.
Abstract: The incidence of cancer is increasing dramatically worldwide. The main treatment for this type of disease is chemotherapy, but the cytotoxicity of chemotherapeutic agents is very high, which generates several side effects for the patient in treatment. Given the limitations of chemotherapy and the increased incidence of this disease, it has been important the study of new substances with antineoplastic action, lower cytotoxic and fewer side effects, providing a better quality of life for the patient. The objective of this study was to determine the antitumor activity of the mesoionic compound Sydnone 1 (Syd-1) using the Walker-256 tumor model in rats, assessing tumor growth and its possible induction of cell death mechanism (apoptosis, oxidative stress and participation in the inflammatory process). Male Wistar rats, weighing between 180 g to 220 g, were used in the experiments. For tumor induction 1x107 neoplastic cells of Walker-256 strain were inoculated subcutaneously in the right leg of animals. In the day after inoculation the treatment started orally (gavage) with Syd-1 at a dose of 75 mgokg-1 or vehicle (20% Tween and saline) to groups: 1) Basal (healthy animals receiving vehicle), 2) Basal-Syd (healthy animals that received Syd-1), 3) Tumor (tumor-bearing animals that received saline) and 4) Tumor-Syd (tumor-bearing animals treated with Syd-1). After 12 days of treatment the animals were anesthetized for blood collection, and then the animals were euthanized, allowing the collection of other tissues. Liver, tumor and blood were collected and frozen for later analysis. In addition, tumor volume and tumor weight were evaluated along the treatment. The compound produced significant tumor suppression in animals of the Tumor-Syd group compared with the Tumor group. Furthermore, there was a decrease in GSH levels in tumor tissue of the treated group, indicating a possible pro-oxidant action of Syd-1 in the tumor. This can be an important mechanism against cancer progression. Biochemical analyzes showned that treatment with Syd-1 tended to alleviate some damage caused by cachexia syndrome, inversely Syd-1 did not present anti-inflammatory effects. The Tumor-Syd group presented increased gene expression of the pro-apoptotic proteins Bax and p53, and decrease of the anti-apoptotic protein Bcl-2 in tumor tissue. These data elucidated the possible Syd-1 mechanism of action, which is the modulation of apoptosis. In animals treated with Syd-1 (Basal-Syd and Tumor-Syd), there was a considerable splenomegaly, which correlates with hematological changes, such as increased MCV, MCH and RDW. Further histology showed in the spleen of the animals receiving Syd-1a significant presence of iron. Thus, the splenomegaly could be a consequence of the hemolysis induced by the compound. In conclusion, this study demonstrates a significant antitumoral action of Syd-1 against the Walker-256 carcinosarcoma and elucidates its mechanism of action, which involves the activation of apoptotic pathways. However, the hematological side effects and the splenomegaly should be better elucidated. Keywords: Cancer, Walker-256, Syd-1, Apoptosis, Splenomegaly.
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Lemos, Sahra Cavalcante [UNESP]. "Compostos de paládio (II): síntese, caracterização e investigação da atividade antitumoral." Universidade Estadual Paulista (UNESP), 2012. http://hdl.handle.net/11449/105780.
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lemos_sc_dr_araiq.pdf: 2082064 bytes, checksum: 81d0ccbd95856119b75521d6f0638d4f (MD5)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Compostos ciclometalados de paládio(II) contendo ligantes derivados das oximas são bastante empregados em catálise, entretanto, pouco se sabe ainda sobre as suas potencialidades biológicas. Em nosso grupo de pesquisa, diversos complexos ciclometalados com ligantes nitrogenados como a N,N-dimetilbenzilamina ou N-benzilidenoanilina foram sintetizados e empregados em ensaios biológicos, apresentando resultados promissores frente a diferentes linhagens celulares tumorais. Destacam-se também os complexos contendo ligantes fosforados e sulfurados, como as fosfinas e as tiouréias. Sendo assim, o presente trabalho descreve a síntese e caracterização de compostos ciclometalados binucleares de Pd(II) do tipo [Pd(bzox)(μ-X)]2, nos quais bzox = benzaldeidoximato e X= Cl (S1), Br (S2) ou SCN (S3), compostos ciclometalados mononucleares neutros do tipo [Pd(bzox)X(im)], em que im = imidazolidina-2-tiona e X = Cl(S4), Br (S5) ou I (S6), compostos ciclometalados mononucleares catiônicos do tipo [Pd(bzox)(L)2]Cl nos quais L = tiouréia (S7), dimetiltiouréia (S8) ou bipiridina (S9) e compostos de coordenação do tipo [PdX2(im)(PPh3)], onde PPh3 = trifenilfosfina e X = Cl (S10), Br (S11), I (S12) ou SCN (S13). As estruturas de tais complexos foram propostas com base em medidas de análise elementar, espectroscopia vibracional no infravermelho e ressonância magnética nuclear. Os complexos S7-S9 não puderam ter as suas estruturas completamente elucidadas, uma vez que não foi possível a obtenção dos espectros de RMN de 1H e bidimensionais dos compostos. Quanto aos complexos S10-S13 não foi possível obter os espectros de RMN de 31P. O comportamento térmico dos complexos S1–S3 e S10–S13 foi investigado por termogravimetria e análise térmica diferencial e as quantidades de resíduos obtidos estão de acordo com as quantidades...
Cyclopalladated compounds bearing oximes derivatives are frequently used as catalysts, however their biological relevance is not well documented. In our research group, many cyclometallated complexes bearing nitrogen donor ligands, such as N,N-dimethylbenzylamine and N-benzilideneaniline, were synthesized and used in biological investigations towards a variety of tumoral cell lines. Promising results were obtained not only for cyclopalladated complexes, but also for coordination compounds bearing phosphines or thiourea derivatives. Thus, this work describes the synthesis and characterization of Pd(II) binuclear cyclometallated compounds of the type [Pd(bzox)(μ-X)]2 (bzox = benzaldeidoxima, X= Cl (S1), Br (S2) or SCN (S3)), neutral mononuclear cyclometallated compounds of the type [Pd(bzox)X(im)] (im = imidazolidine-2-thione, X = Cl (S4), Br (S5) or I (S6)), cationic cyclometallated compounds of the type [Pd(bzox)(L)2]Cl (L = thiourea (S7), dimethylthiourea (S8) or bipyridine (S9) and coordination compounds of the type [PdX2(im)(PPh3)] (PPh3 = triphenylphosphine, X = Cl (S10), Br (S11), I (S12) or SCN (S13). Structure proposals were suggested based on results of C, H, N elemental analysis, infrared spectroscopy and nuclear magnetic resonance. The NMR spectra of complexes 7-9 could not be obtained and consequently, their structures could not be completely elucidated. The 31P NMR spectra were not recorded either. The thermal behavior of complexes S1–S3 and S10–S13 was investigated by thermogravimetry and differential thermal analysis. Important information was obtained from residual mass values from each analysis, supporting the stoichiometry proposed for the structures of the complexes. The citotoxicity of compounds S1 and S4–S6 towards MM3 cell line (murine mammary adenocarcinoma) was... (Complete abstract click electronic access below)
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Fernandes, Thais Batista. "Planejamento, síntese e avaliação do potencial antitumoral de compostos arilsulfonil-hidrazônicos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-01102015-134701/.
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A capsaicina é um componente pungente das pimentas do gênero capsicum que possui atividade antitumoral. Na busca por compostos antineoplásicos mais eficazes e seletivos em relação aos disponíveis atualmente, foi desenvolvido um análogo sulfonamídico sintético da capsaicina, o RPF101, que apresentou atividade citotóxica superior em linhagens de adenocarcinoma de mama. Face ao exposto, o objetivo deste trabalho foi otimizar a atividade do RPF101 a partir da síntese de análogos sulfonil-hidrazônicos planejados por bioisosterismo. Treze análogos foram sintetizados em três etapas, baseando-se na reação entre cloreto de sulfonila e hidrato de hidrazina para obtenção do intermediário sulfonil-hidrazida; oxidação do álcool piperonílico para obtenção do piperonal; e reação de adição nucleofílica entre sulfonil-hidrazida e piperonal ou vanilina, que apresentaram rendimentos entre 23 e 85%. Os compostos foram caracterizados por metodologias de RMN 1H/13C, faixa de fusão e análise elementar e avaliados quanto sua capacidade citotóxica em células de adenocarcinoma de mama (MDA-MB-231 e MCF-7) pelo método do MTT. Dois análogos mostraram-se ativos nas duas linhagens, dos quais o mais promissor, RPF906 (IC50 em MDA-MB-231 = 104,6 µM) foi submetido a estudos de elucidação mecanística, onde observou-se indução de apoptose, causando interrupção do ciclo celular na fase G0/G1. Os resultados obtidos mostraram que o grupo benzodioxol favorece a atividade biológica quando comparado ao grupo metilcatecol. Estudos de modelagem molecular sugerem que uma maior hidrofilicidade esteja relacionada com uma atividade superior. Embora menos ativas que seu protótipo, as sulfonil-hidrazonas apresentaram efeito biológico e mostram-se promissoras no desenvolvimento de compostos com potencial antitumoral. Novas modificações moleculares devem ser planejadas com o intuito de otimizar a atividade e seletividade destes compostos.Capsaicin is a primary pungent compound in red peppers, which has antitumor activity. In view of demand for more selective and less toxic anticancer agents, our group reported a synthetic sulfonamide capsaicin-like analogue, RPF101, which presents higher cytotoxicity in adenocarcinoma cell line than its prototype. Thus, the aim of this work is to optimize RPF101 activity by the synthesis of sulfonylhydrazone analogues, using the bioisosterism as molecular modification strategy. Thirteen analogues were synthesized in three reaction steps: oxidation of piperonyl alcohol to the piperonyl aldehyde; nucleophilic substitution reaction between sulfonyl chloride and hydrazine hydrate to obtain the intermediate sulfonylhydrazide; nucleophilic addition reaction between sulfonylhydrazide and piperonal of vanilin to obtain sulfonylhydrazones, which showed yields between 23 and 85%. All compounds were characterized by NMR 1H/13C, melting point and elemental analisys and evaluated for their cytotoxic activity in breast tumor cell lines (MDA-MB-231 and MCF-7). Two analogues showed cytotoxic effect although RPF906 (IC50 in MDA-MB-231= 104.6 µM) had been the most promising and was further evaluated about its mechanistic properties. This compound induced apoptosis and cell cycle arrest at the G0/G1 phase. Results showed that the introduction of benzodioxol group increases cytotoxicity. Molecular modeling studies suggests that superior hydrophilicity is related to superior activity. Sulfonyl-hydrazone analogues were less cytotoxic than their prototype, but they are still promising compounds. Molecular modifications strategies should be done to optimize the activity and selectivity of these compounds.
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Lemos, Sahra Cavalcante. "Compostos de paládio (II) : síntese, caracterização e investigação da atividade antitumoral /." Araraquara, 2012. http://hdl.handle.net/11449/105780.
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Orientador: Adelino Vieira de Godoy NettoCoorientador: Antonio Eduardo Mauro
Banca: Nivaldo Boralle
Banca: Alexandre de Oliveira Legendre
Banca: Sérgio Roberto de Andrade Leite
Banca: Pedro Paulo Corbi
Resumo: Compostos ciclometalados de paládio(II) contendo ligantes derivados das oximas são bastante empregados em catálise, entretanto, pouco se sabe ainda sobre as suas potencialidades biológicas. Em nosso grupo de pesquisa, diversos complexos ciclometalados com ligantes nitrogenados como a N,N-dimetilbenzilamina ou N-benzilidenoanilina foram sintetizados e empregados em ensaios biológicos, apresentando resultados promissores frente a diferentes linhagens celulares tumorais. Destacam-se também os complexos contendo ligantes fosforados e sulfurados, como as fosfinas e as tiouréias. Sendo assim, o presente trabalho descreve a síntese e caracterização de compostos ciclometalados binucleares de Pd(II) do tipo [Pd(bzox)(μ-X)]2, nos quais bzox = benzaldeidoximato e X= Cl (S1), Br (S2) ou SCN (S3), compostos ciclometalados mononucleares neutros do tipo [Pd(bzox)X(im)], em que im = imidazolidina-2-tiona e X = Cl(S4), Br (S5) ou I (S6), compostos ciclometalados mononucleares catiônicos do tipo [Pd(bzox)(L)2]Cl nos quais L = tiouréia (S7), dimetiltiouréia (S8) ou bipiridina (S9) e compostos de coordenação do tipo [PdX2(im)(PPh3)], onde PPh3 = trifenilfosfina e X = Cl (S10), Br (S11), I (S12) ou SCN (S13). As estruturas de tais complexos foram propostas com base em medidas de análise elementar, espectroscopia vibracional no infravermelho e ressonância magnética nuclear. Os complexos S7-S9 não puderam ter as suas estruturas completamente elucidadas, uma vez que não foi possível a obtenção dos espectros de RMN de 1H e bidimensionais dos compostos. Quanto aos complexos S10-S13 não foi possível obter os espectros de RMN de 31P. O comportamento térmico dos complexos S1-S3 e S10-S13 foi investigado por termogravimetria e análise térmica diferencial e as quantidades de resíduos obtidos estão de acordo com as quantidades... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Cyclopalladated compounds bearing oximes derivatives are frequently used as catalysts, however their biological relevance is not well documented. In our research group, many cyclometallated complexes bearing nitrogen donor ligands, such as N,N-dimethylbenzylamine and N-benzilideneaniline, were synthesized and used in biological investigations towards a variety of tumoral cell lines. Promising results were obtained not only for cyclopalladated complexes, but also for coordination compounds bearing phosphines or thiourea derivatives. Thus, this work describes the synthesis and characterization of Pd(II) binuclear cyclometallated compounds of the type [Pd(bzox)(μ-X)]2 (bzox = benzaldeidoxima, X= Cl (S1), Br (S2) or SCN (S3)), neutral mononuclear cyclometallated compounds of the type [Pd(bzox)X(im)] (im = imidazolidine-2-thione, X = Cl (S4), Br (S5) or I (S6)), cationic cyclometallated compounds of the type [Pd(bzox)(L)2]Cl (L = thiourea (S7), dimethylthiourea (S8) or bipyridine (S9) and coordination compounds of the type [PdX2(im)(PPh3)] (PPh3 = triphenylphosphine, X = Cl (S10), Br (S11), I (S12) or SCN (S13). Structure proposals were suggested based on results of C, H, N elemental analysis, infrared spectroscopy and nuclear magnetic resonance. The NMR spectra of complexes 7-9 could not be obtained and consequently, their structures could not be completely elucidated. The 31P NMR spectra were not recorded either. The thermal behavior of complexes S1-S3 and S10-S13 was investigated by thermogravimetry and differential thermal analysis. Important information was obtained from residual mass values from each analysis, supporting the stoichiometry proposed for the structures of the complexes. The citotoxicity of compounds S1 and S4-S6 towards MM3 cell line (murine mammary adenocarcinoma) was... (Complete abstract click electronic access below)
Doutor
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Melo, Andréa Lopes. "Síntese de novos compostos acridínicos e mostardas com potencial atividade antitumoral." Universidade Federal de Alagoas, 2015. http://www.repositorio.ufal.br/handle/riufal/1566.
Повний текст джерелаАнотація:
Cancer is a disease that kills the world and it is estimated that in 2030 the incidence of this disease in the world reach 21.4 million new cases with 13.2 million deaths. Due to the resistance, non-selectivity and high cytotoxicity, many of the current drugs produce side effects such as bone marrow depression, sterility, risk of non-lymphocytic leukemia, among others. Thus it is necessary to the development of new anticancer drugs that have less harmful effects. Thus, six new compounds were synthesized, four acridínicos derivative, a derivative of bis (cloroetila) and palladium (II) complex acridínico, whose acronyms, respectively (Acri)2N, AcriPro, ACDMA, ACBr2MAN, (Most)2N and ACDMAPd. All these compounds derived from Schiff base had satisfactory yields and characterized by NMR techniques (1H, 13C, COSY, J solved) spectroscopy in the infrared, mass spectrometry and elemental analysis. The strains used human tumor cells were HT-29 (human colon cancer), MCF-7 (human breast cancer), Hep-2 (human larynx carcinoma), NCI-H292 (carcinoma human pulmonary mucoepidermoid) and HL -60 (acute promyelocytic leukemia) and derivatives AcriPro, ACDMA, (Most)2N and ACDMAPd showed the best results of IC50 for the HL-60 cells.Conselho Nacional de Desenvolvimento Científico e Tecnológico
O câncer é uma das doenças que mais mata no mundo e estima-se que em 2030 a incidência no mundo desta doença alcance 21,4 milhões de novos casos com 13,2 milhões de mortes. Devido à resistência, a não seletividade e a alta citotoxicidade, grande parte dos fármacos atuais produzem efeitos indesejáveis tais como: depressão na medula óssea, esterilidade, risco de leucemia não linfocítica, entre outros. Desta forma faz-se necessário o desenvolvimento de novos fármacos antitumorais que possuam menos efeitos agressivos. Assim, foram sintetizados seis novos compostos, sendo quatro derivados acridínicos, um derivado bis(cloroetila) e um complexo de paládio(II) acridínico, que tem como acrônimos, respectivamente, (Acri)2N, AcriPro, ACDMA, ACBr2MAN, (Most)2N e ACDMAPd. Todos esses compostos derivados de base de Schiff tiveram rendimentos satisfatórios e foram caracterizados pelas técnicas de RMN (1H, 13C, COSY, J resolvido), espectroscopia na região do infravermelho, espectrometria de massas e Análise Elementar. As linhagens de células tumorais humanas utilizadas foram HT-29 (câncer de cólon humano), MCF-7 (câncer de mama humano), HEp-2 (carcinoma de laringe humana), NCI-H292 (carcinoma mucoepidermoide de pulmão humano) e HL-60 (leucemia promielocitica aguda) e os derivados AcriPro, ACDMA, ACDMAPd e (Most)2N apresentaram os melhores resultados de CI50 para a células HL-60.
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Miguel, Rodrigo Bernardi. "Alvos intracelulares e mecanismos de ação de complexos de cobre(II) ou zinco(II) oxindolimínicos com atividade antitumoral." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/46/46136/tde-20072018-091019/.
Повний текст джерелаАнотація:
No presente trabalho foram realizados estudos da atividade biológica de complexos imínicos de Cu(II) e Zn(II) derivados da isatina, principalmente frente a células tumorais HeLa. Sabe-se que estes complexos se ligam ao DNA, podendo causar clivagens simples e duplas na sua estrutura, em presença de peróxido de hidrogênio, através de um mecanismo predominantemente oxidativo. Os complexos de Cu(II) geram espécies reativas de oxigênio (EROs) e, além disto, atuam sobre a mitocôndria como agentes desacopladores. Sabe-se ainda que esses compostos interagem com proteínas específicas, como por exemplo a topoisomerase humana IB e as quinases dependentes de ciclinas (CDKs), inibindo significativamente sua atividade, ou a proteassoma, frente à qual apenas uma inibição moderada foi observada. Os ensaios in vitro desenvolvidos nesta tese, permitiram evidenciar a capacidade de os complexos de intercalar no DNA e RNA, além de clivar o primeiro biopolímero. Os resultados obtidos in celullo, evidenciaram a dependência do cobre para a citotoxicidade dos complexos sendo estes compostos capazes de estimular a necrose das células HeLa. Além disso, os resultados demonstraram que estes compostos são capazes de interferir no ciclo celular, interrompendo-o em fase G2/M e de desencadear um desequilíbrio oxidativo. Os principais alvos intracelulares dos complexos, em células HeLa, são a Mitocôndria, pois interferem em seu funcionamento diminuindo o seu potencial de membrana, e o DNA clivando-o. Ademais, pretendeu-se, através de um estudo sistemático por microscopia Raman confocal, identificar danos celulares provocados pelos complexos, especialmente uma grande alteração no núcleo celular de células HeLa após o tratamento com o complexo [Cu(isaepy)]+. Através de ensaios de viabilidade, também foi possível demonstrar que a superexpressão de glicoproteína-P para linhagem MES-AS/Dx5 não resulta na resistência dessas células frente aos compostos testados, e que os complexos não interferem no funcionamento desta glicoproteína. Também foi observado, através dos experimentos com células HaCaT, que o complexo [Zn(isaepy)]2+ é capaz de interferir no ciclo autofágico celular.In the present work, the synthesis and characterization of oxindolimine complexes of Cu(II) and Zn(II) were carried out. R is known that these complexes bind to DNA and can cause single and double cleavages in their structure, in the presence or absence of hydrogen peroxide, through a predominantly oxidative mechanism. Cu(II) complexes generate reactive oxygen species (ROS) and, in addition, act on mitochondria as decoupling agents. These compounds are also known to interact with specific proteins, such as human topoisomerase IB and cyclin-dependent kinases (CDKs), inhibiting significantly their activity, or the proteasome, against which only moderate inhibition has been observed. The in vitro assays developed in this thesis have demonstrated the ability of these complexes in intercalating at DNA and RNA, in addition to cleaving the first biopolymer. The results in cellulo evidenced the dependence on the copper for the cytotoxicity of the complexes, that can stimulate the necrosis in HeLa cells. In addition, the results demonstrated that these compounds are capable of interfering in the cell cycle, stopping it at G2/M phase and triggering an oxidative imbalance. The main intracellular targets of the complexes, in HeLa cells, are the Mitochondria, where they interfere in its function, diminishing its membrane potential, and the DNA, causing its cleavage. Further, it was intended, through a systematic study by confocal Raman microscopy, to identify cellular damage triggered by the complexes. Particularly, a large change in the cell nucleus of HeLa cells was demonstrated after treatment with the \'[Cu(isaepy)] POT.+\' complex. Through viability assays, it was also demonstrated that overexpression of P-glycoprotein in MES-SA/Dx5 lineage does not result in the resistance of these cells to the tested compounds, and that the complexes do not interfere in the functioning of this glycoprotein. Finally, it was observed, in experiments with HaCaT cells, that \'[Zn(isaepy)] POT.2+\' complex can interfere in the autophagic cell cycle.
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Paiva, Raphael Enoque Ferraz de 1989. "Complexos metálicos com nimesulida : síntese, caracterização e aplicações em química bioinorgânica medicinal." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249124.
Повний текст джерелаАнотація:
Orientador: Pedro Paulo CorbiDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: Complexos metálicos têm sido estudados quanto as suas propriedades medicinais há décadas. Neste trabalho, dois complexos inéditos de Ag(I) e Pt(II) foram sintetizados com o anti-inflamatório nimesulida (NMS), e avaliados como agentes antibacterianos e antitumorais. O complexo Ag-NMS (AgC13H11N2O5S) apresenta o ligante em uma coordenação bidentada à prata pelos átomos de N e O do grupo sulfonamida. A estrutura proposta foi confirmada por DFT. Devido à baixa solubilidade em água, foi preparado um complexo de inclusão de Ag-NMS em b-CD, pelo método de co-evaporação. Utilizando o método de Scatchard, foi determinado o valor de Ka = 370 2 L mol. Estudos de RMN por correlação H-H através do espaço mostram que a inclusão ocorre pelo grupo fenoxi da NMS. Já o complexo Pt-NMS (PtC26H22N4O10S2) apresenta dois ligantes, coordenados pelos átomos de N e O do grupo sulfonamida, para cada Pt(II). A DFT indica que o isômero N, O trans é o mais estável. O complexo Ag-NMS apresentou valores de MIC na faixa de 15,0-120 mmol L sobre cepas de Pseudomonas aeruginosa, Escherichia col e Staphylococcus aureus. O CE-[(Ag-NMS)·b-CD], embora mais solúvel em água do que o Ag-NMS, não apresentou atividade antibacteriana nas concentrações testadas. Os complexos Ag-NMS e Pt-NMS mostraram-se citotóxicos sobre células normais (Balb/c 3T3) e tumorais (SK-Mel 103 e Panc-1), porém o Pt-NMS foi significativamente mais seletivo contra as linhagens tumorais. Os ensaios de intercalação com EtBr e a avaliação da estrutura do DNA por dicroísmo circular indicam que o DNA não é um alvo biológico para o complexo Pt-NMS, indicando um mecanismo de ação diferente da cisplatina
Abstract: Metal complexes have been studied regarding its medicinal properties for decades. In this work, novel complexes of Ag(I) and Pt(II) with the anti-inflammatory nimesulide were synthesized and evaluated regarding their antibacterial and antitumoral properties. The Ag-NMS complex (AgC13H11N2O5S) shows the ligand in a bidentate coordination mode, bound to silver through the N and O atoms of the sulfonamide group. The proposed structure was confirmed by DFT. Due to its poor solubility in water, the Ag-NMS complex was included in b-CD, by co-evaporation. The Ka = 370 2 L mol was determined using the Scatchard method. Studies by H-H NMR correlation through space shows the inclusion of NMS by the fenoxi group. The Pt-NMS complex (PtC26H22N4O10S2) contain two ligands, coordinated through the N and O atoms of the sulfonamide group, for each Pt(II). DFT studies indicate that the N,O trans isomer is the most stable. The Ag-NMS complex presents MIC values in the range 15.0-120 mmol L over Pseudomonas aeruginosa, Escherichia coli e Staphylococcus aureus. The inclusion complex CE-[(Ag-NMS)·b-CD], although more soluble in water than Ag-NMS, shows no antibacterial activity in the tested concentrations. Both complexes were cytotoxic against normal (Balb/c 3T3) and tumor (SK-Mel 103 and Panc-1) cells, but the Pt-NMS complex was significantly more selective against tumor cells. The EtBr competitive intercalation assay and the evaluation of CT-DNA structure using circular dichroism show that DNA is not a biological target for the Pt-NMS complex, indicating a mechanism of action different of the cisplatin one
Mestrado
Quimica Inorganica
Mestre em Química
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RUIZ, NICOLAS. "Synthese de composes polycycliques a structure benzodioxinique : elaboration de derives a activite antitumorale potentielle." Orléans, 1995. http://www.theses.fr/1995ORLE2026.
Повний текст джерелаАнотація:
Au cours de ce travail, nous nous sommes interesses a la synthese de composes polycycliques presentant une sous-unite benzodioxinique. Pour cela, deux strategies ont ete envisagees. La premiere met en uvre des reactions de metallation et d'acylation a partir de substrats benzodioxiniques. Une voie utilisant le 2-carboxy-1,4-benzodioxine comme substrat n'a pu etre menee a bien. Lorsque le substrat est la 1,4-benzodioxine, des reactions de metallation ont conduit a des derives tetracycliques avec des rendements toutefois mediocres. Ceci nous a incite a developper une seconde strategie, de type diels alder. Differents systemes dieniques benzodioxiniques et furobenzodioxiniques ont ete obtenus, et engages dans des reactions de cycloaddition 4+2. L'aromatisation des adduits, bien que souvent problematique, a pu etre menee a bien, soit en milieu acide, soit en milieu basique, pour conduire aux dibenzodioxines correspondantes. Ces dernieres possedent des fonctionnalites diverses, placees regioselectivement, et permettent d'envisager l'acces a des composes possedant une activite pharmacologique potentielle. Ainsi la synthese de composes benzodioxinoisoquinoliniques, analogues structuraux des pyridocarbazoles de la serie de l'ellipticine a ete realisee. Cette strategie de type diels alder s'est donc revelee tres efficace. Un des derives synthetise, a ete obtenu en quantite suffisante pour initier une serie de tests in vitro et in vivo, afin d'evaluer ses proprietes antitumorales
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Christophe, Stéphanie. "Synthèse arynique de biphénylènes, benzo cyclobuta biphénylènes et benzo cyclobuta carbazoles : obtention de nouveaux antitumoraux." Nancy 1, 1998. http://www.theses.fr/1998NAN10112.
Повний текст джерелаАнотація:
Dans une première partie, des synthèses de biphénylènes et de benzo cyclobuta biphénylènes ont été réalisées par cyclisations aryniques intermoléculaires d'énolates de cétones sur des dérivés halogènes aromatiques au moyen des bases complexes NaNH2/tBuONa. Des études systématiques ont permis de trouver les conditions optimales d'obtention des produits recherches. Ainsi, une gamme de dérivés pentacycliques bis hydroxylés fonctionnalisés ou fonctionnalisables a pu être synthétisée à partir de matières premières peu onéreuses avec un principe réactionnel assez simple. Dans une deuxième partie, la cyclisation arynique intermoléculaire d'énolates de tétrahydro carbazolones sur des dérivés halogènes aromatiques grâce aux bases complexes NaNH2/tBuONa a permis d'obtenir une nouvelle famille de composés : les benzo cyclobuta carbazol-ol. Une deuxième voie d'accès à ces composés a été mise au point et consiste en la cyclisation intramoléculaire d'iminobiphénylénones au moyen des bases complexes. Ces composés ont ensuite été soumis à divers agents de déshydratation et ont conduit aux dérivés éthyléniques correspondants facilement aromatisables. Une étude exploratoire a permis de montrer que la fonctionnalisation de ces composés aromatiques était envisageable. Des tests réalisés par des pharmacologues sur ces composés ainsi obtenus ont permis de mettre en évidence une activité antitumorale sur les cellules L 1210 mais également une action sur le cycle cellulaire.
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Antoine, Maud Le Baut Guillaume Marchand Pascal. "Synthèse et évaluation pharmacologique de composés indoliques et pyridopyraziniques à visée antitumorale." [S.l.] : [s.n.], 2005. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=26641.
Повний текст джерела
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Moura, Thales Reggiani de [UNESP]. "Compostos de Pd(II) contendo ligantes N,S-doadores: síntese, caracterização e estudo da atividade citotóxica." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/137769.
Повний текст джерелаАнотація:
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Nos últimos anos, o interesse na obtenção de novos fármacos à base de metais visando o tratamento de cânceres vem aumentando consideravelmente. A descoberta da atividade antitumoral da cisplatina e seu subsequente sucesso como fármaco no tratamento do câncer inspirou o estudo de inúmeros complexos análogos, que apresentaram, em geral, padrões similares de atividade antitumoral e susceptibilidade à resistência. Por apresentarem mesmas configuração eletrônica e geometria em relação à compostos de Pt(II), compostos de coordenação contendo o íon Pd(II) foram amplamente estudados, sendo reconhecido para os compostos de Pd(II) contendo ligantes N,S-doadores, modos de ação distintos em relação ao compostos de Pt(II). Neste trabalho foram sintetizados e caracterizados 4 novos complexos de paládio(II) do tipo [PdX(tedmPz’)(PPh3)] {tedmPz’ = N-etil-1-iminotiolato-3,5-dimetilpirazol; X = Cl-, Br-, I-, SCN-; PPh3 = trifenilfosfina}. Os complexos foram caracterizados pelas técnicas de espectroscopia vibracional na região do IV e RMN de 1H e 13C, análise elementar, espectrometria de massas ESI/MS e difração de raios X de monocristal, indicando um ambiente quadrático plano ao redor do metal, com seus sítios de coordenação ocupados pela trifenilfosfina, e pelo ligante tedmPz coordenado de maneira N,S-aniônica e ligante tiocianato ligado de modo N-terminal. Também é descrita a síntese e caracterização espectroscópica na região do IV e RMN de 1H e 13C do ligante tedmPz. A citotoxicidade in vitro do ligante e de todos os complexos foi avaliada pelo método do MTT, frente as culturas celulares de tumores murinos MCF-7 (adenocarcinoma mamário humano). Todos os compostos tiveram sua capacidade de interação com um nucleosídeo (guanosina) investigada com o objetivo de avaliar sua possível interação covalente com o DNA. Os resultados obtidos indicaram que a variação dos ligantes haletos não interferiu na citotoxicidade dos complexos, bem como os compostos sintetizados não apresentaram capacidade de interagir com a guanosina, sendo esta uma evidência preliminar de que a interação covalente entre os compostos sintetizados e a guanina presente no DNA não é o mecanismo de citotoxicidade destes. Vale destacar que todos os compostos foram mais citotóxicos que a cisplatina, obtendo-se em média valores de IC50 de até 2,4 vezes menor que o fármaco de comparação.
In the last years, the interest of new drugs based on metals in order to treat cancers has been increasing considerably. The discovery of cisplatin antitumor activity and its subsequent success as a cancer treatment drug has inspired the study of several analogous compounds, which presented, in general, similar patterns of antitumor activity and susceptibility to resistance. By presenting the same electronic configuration and geometry of Pt(II) complexes, coordination complex containing Pd (II) ion have been extensively studied, and recognized different activity patterns for these compounds containing ligands N,S-donor in relation to compounds of Pt (II). In this work, were synthesized and characterized four novel complexes of palladium(II) type [PdX(tedmPz')(PPh3)] {tedmPz' = N-ethyl-1-iminothiolate-3,5-dimethylpyrazole; X = Cl-, Br-, I-, SCN-; PPh3 = triphenylphosphine}. The complexes were characterized by vibrational spectroscopy techniques in the IV region and 1H NMR and 13C NMR, elemental analysis, mass spectrometry ESI / MS and X-ray diffraction of single crystal, indicating a square planar environment around the metal with its sites coordination occupied by triphenylphosphine, the N,S-anionic coordination of tedmPz ligand, the N-terminal coordination mode of thiocyanate. It is also described the synthesis and spectroscopic characterization in the IV region and 1H NMR and 13C for the tedmPz compound. The in vitro cytotoxicity of the ligand and all of the complexes were evaluated by the MTT method, against the cell cultures of murine tumors MCF-7 (human breast adenocarcinoma). All compounds had their ability to interact with a nucleoside (guanosine) investigated with the objective of evaluating their possible covalent interaction with DNA. The results indicated that the variation of halide ligands did not affect the cytotoxicity of the complexes and the synthesized compounds showed no ability to interact with guanosine, which is a preliminary evidence that covalent interaction between the synthesized compounds and the DNA is not the main source of cytotoxicity of these. It is noteworthy that all the compounds were more cytotoxic than cisplatin, obtaining an average of IC50 values of up to 2.4 times lower than the comparison drug.
CNPq: 132644/2014-2
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Bromberg, Natalia. "Atividade antitumoral de metabolitos bacteriano e fungico." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248927.
Повний текст джерелаАнотація:
Orientador: Nelson Eduardo Duran CaballeroTese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
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Resumo: Os potenciais imuno e quimioterapêutico de dois compostos, o imunomodulador agregado protéico de fosfolinoleato-palmitoleato de amônio e magnésio (P-MAPA) produzido por Aspergillus oryzae e o pigmento citotóxico violaceína, produzido pela Chromobacterium violaceum, foram avaliados neste trabalho. Para tanto, foram utilizados os modelos experimentais murinos do carcinoma renal (RENCA), tumor ascítico de Ehrlich (TAE), carcinoma pulmonar de Lewis (3LL) e linhagens de células endoteliais e da leucemia mielocítica humana (HL60). Resultados obtidos em experimentos in vivo sugeriram atividade antitumoral para a violaceína nas doses de 0,1 e 1,0 mg kg no modelo experimental do TAE, enquanto o composto P-MAPA, na dose de 5 mg kg, também apresentou atividade nos modelos RENCA e 3LL. Além disso, observou-se uma redução no número de metástases pulmonares no grupo de animais inoculados com RENCA e tratados com P-MAPA após a nefrectomia do rim contendo o tumor primário, indicando uma contribuição do composto em protocolos de tratamento de doença residual. Alguns aspectos dos mecanismos envolvidos nestas respostas também foram investigados pela análise de diferentes parâmetros celulares e moleculares in vitro e/ou in vivo como a indução de apoptose, atividade de células "natural killer" e produção de citocinas. O estudo da citotoxicidade da violaceína em culturas de células RENCA, TAE e HL60 demonstrou a indução de processo apoptótico como mecanismo de ação da droga. A apoptose foi estudada utilizando-se a reação de Feulgen, determinação de fragmentação de DNA, avaliação da atividade de caspases, ensaio de marcação com Anexina V/PI, alterações na expressão da proteína Bcl-2 e no potencial transmembrana mitocondrial (Dy). O potencial antitumoral demonstrado nesta tese para os metabólitos estudados reforça a possibilidade de aplicação na terapêutica contra o câncer, sendo ainda promissor considerá-Ios em estudos futuros de terapia combinada
Abstract: The immuno and chemotherapeutic potentials of two natural compounds, the proteic aggregated polymer of magnesium ammonium phospholinolate-palmitoleate anhydride (P-MAPA) isolated from Aspergillus oryzae and the cytotoxic violacein isolated from Chromobacterium violaceum, were evaluated in the present work. The murine renal cancer model (RENCA), the Ehrlich ascites tumor (EAT), the Lewis lung carcinoma (3LL), human and murine endothelial cells and the human myelocitic leukemia cell line (HL60) were used as experimental models. The results from in vivo experiments suggested an antitumoral activity for violacein in EAT-bearing mice treated with 0.1 and 1.0 mg kg, whereas the P-MAPA compound, administrated at 5 mg kg doses, also extended the survival of RENCA-bearing mice and 3LL tumors. A reduced number of pulmonary metastases was observed in the group of RENCA-bearing mice treated with P-MAPA after nephrectomy of the primary tumor-bearing kidney, suggesting that it may be useful in therapeutic approaches to treat the residual disease. Some aspects of the mechanisms involved in these responses were investigated by analysis of different in vivo and/or in vitro cellular and molecular parameters such as apoptosis induction, natural killer cell activity and cytokine production. The study of violacein cytotoxicity on RENCA, EAT and HL60 cell cultures indicated the induction of apoptosis as a mechanism of action. Several techniches were used to charaeterize the apoptotic process such as Feulgen reaction, determination of DNA fragmentation, evaluation of caspase activity, flow cytometry Annexin V/PI assay, evaluation of BcI-2 protein expression and changes in the mitochondrial transmembrane potential (Dy). The antitumoral potential of these metabolites, as demonstrated in this work, reinforces the possibility of their application on cancer therapeutics and in future studies of combined therapy
Doutorado
Físico-Química
Doutor em Ciências
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González, Bártulos Marta. "Estudi de l'activitat antitumoral de nous compostos basats en metalls de transició." Doctoral thesis, Universitat de Girona, 2017. http://hdl.handle.net/10803/620757.
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Nowadays, cancer is one of the leading causes of death in developed countries. Therefore, there is great interest of developing new therapeutic strategies to improve the efficiency of current cancer treatments. The vulnerability of cancer cells to oxidative stress may be a therapeutic target for new anti-cancer agents design. Differential redox homeostasis in normal and malignant cells suggests that promoting upregulation of cellular reactive oxygen species (ROS) by pro-oxidant treatment could selectively target cancer cells without compromising the viability of healthy cells.
The complexes generated in the cells showed a high capacity to induce DNA double-strand breaks through oxidative mechanisms, suggesting oxidative dependent mechanisms as its major biological targets. This activity has been demonstrated at both molecular (DNA plasmid) and cellular levels. In summary, the present work has characterized the mechanism by which the complexes exhibit anti-tumor activity against a large number of cell lines. This mechanism includes intracellular iron chelation and subsequent pro-oxidant activity by intracellular generated iron complexes. These complexes display a potent cytotoxic activity both in tumor cells and metastatic tumor stem cell-like. Therefore, altogether the results shown throughout the project provide functional evidences of a new family of metallodrugs with efficient anti-tumor activity aimed to disrupt tumor cell redox balance triggering cell death by oxidative-dependent mechanismsEn l’actualitat el càncer és una de les principals causes de mort en els països desenvolupats i per tant, hi ha un enorme interès en desenvolupar noves estratègies terapèutiques que millorin l’efectivitat dels actuals tractaments antitumorals. S’ha descrit que les alteracions metabòliques de les cèl·lules tumorals fan que estiguin sotmeses a un major estrès oxidatiu que les cèl·lules sanes i per tant són més vulnerables a agents pro-oxidants que puguin alterar el seu equilibri redox. Darrerament, aquesta diferència en l’estat redox s’està explorant com a diana pel desenvolupament de nous tractaments pel càncer. En aquest context, ens vam proposar analitzar l’activitat antitumoral de diferents famílies de complexes amb metalls de transició amb base aminopiridina que actuen com a eficients i robusts catalitzadors d'oxidació de substrats orgànics. Hem vist que aquests complexes presenten una elevada capacitat per induir talls en la doble cadena de DNA mitjançant mecanismes oxidatius, el que indica que aquest és una de les seves principals dianes biològiques. Aquesta activitat s’ha demostrat tant directament a nivell de DNA plasmídic com a nivell cel·lular. En resum, aquest estudi ha permès caracteritzar el mecanisme pel qual els compostos presenten una activitat antitumoral contra un elevat nombre de tipus cel·lulars. Aquest mecanisme inclou la quelació del ferro intracel·lular i la posterior activitat pro-oxidant dels complexes de ferro generats intracel·lularment, els quals exerceixen una potent activitat citotòxica tant en cèl·lules tumorals com en cèl·lules mare tumorals, causants de la metàstasi. Per tant, els resultats obtinguts en l’estudi proporcionen evidències funcionals d’una nova família de metal·lodrogues amb una eficient activitat antitumoral dirigida a alterar l’estat redox de les cèl·lules tumorals i a generar la seva mort per mecanismes oxidatius
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Santos, Thaís Rosa Marques dos. "Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562." Universidade Federal de Goiás, 2016. http://repositorio.bc.ufg.br/tede/handle/tede/6756.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Although the efforts employed by scientific community to discover new anticancer therapies suitable to the increasing cancer incidence and multidrug resistance, its necessary to develop more selective and target driven drugs. Therefore, in this work we have done a screening with LQFM030 analogues, which is a Nutlin-1 analogue, aiming to evaluate their cytotoxic potential. Furthermore, we have evaluated the cytotoxicity, the morphological alterations and the cell death induction mechanisms of the compound LQFM166 in leukemia cell line K562. In parallel, we have investigated the security profile of the compound upon 3T3 basal cell line to estimate its LD50 and the Selectivity Index. The cytotoxicity assays included the tetrazolium salt (MTT) reduction and the Neutral Red Uptake assays, to assess the cytotoxicity of LQFM166 in K562 and 3T3 cell lines, respectively. The investigation of cell death induction mechanisms was carried out using flow cytometry, whereby we have evaluated the cells biochemistry parameters, including cell cycle progression, phosphatidylserine externalization, caspases 3/7, 8 and 9 activity, cytochrome c release from mitochondria, p21, p27, Bax, Bcl-2, cyclin-B1 and NFkB expression, using specific labeling for each assay. Data were analyzed by t test and the difference between control and treated groups averages was considered statistically significant when p<0,05. Regarding leukemia cell line K562, the compound LQFM166 was cytotoxic, showing a dose-time-dependent profile. Morphological alterations were observed after treatment with the compound at cellular and nuclear levels, which corroborate with apoptotic cell death. Additionally, treatment with the IC50 for 48 hours has promoted cellular and molecular changes that characterize this process, including phosphatidylserine externalization, increase of caspases 3/7, 8 and 9 activity, expression of pro-apoptotic proteins Bax, p21and p27, as well as diminution of Bcl-2 and cyclin-B1. We have also observed increase of cytochrome-c release and NFkB expression. Concerning the security profile, the compound was considered relatively selective, once the IC50 found to basal cell line (185,3 µM) was the double of the obtained to leukemia cell line regarding the same time of exposure (56,76 µM). The outcomes allow us to conclude that LQFM166 was cytotoxic upon leukemia cells K562, promoting morphological and biochemical alterations that indicate apoptotic cell death induction.
Mesmo com os esforços da comunidade científica em descobrir ou desenvolver medicamentos adequados a crescente incidência do câncer e ainda adequados à suas formas multirresistentes, é necessário o desenvolvimento de medicamentos que sejam seletivos e alvo-dirigidos. Assim, no trabalho proposto, foi realizada uma triagem com compostos análogos ao LQFM030, análogo estrutural do Nutlin-1, visando determinar o potencial citotóxico dos mesmos. Além disso, foram investigados a citotoxicidade, as alterações morfológicas e os mecanismos de indução de morte celular do composto escolhido LQFM166 em linhagem de células leucêmicas K562. Paralelamente, foi investigado o perfil de segurança do composto sobre a linhagem basal 3T3, a fim de estimar a DL50 e o Índice de Seletividade do mesmo. Os ensaios de citotoxicidade incluíram o método de redução do sal de tetrazólio (MTT) e o método de incorporação do corante vermelho neutro, para a avaliação do potencial citotóxico sobre as linhagens K562 e 3T3, respectivamente. Para a investigação dos mecanismos de indução de morte celular foi utilizada a técnica de citometria de fluxo, por meio da qual foi realizada a avaliação de parâmetros bioquímicos incluindo progressão ciclo celular, externalização da fosfatidilserina, atividade das caspases 3/7, 8 e 9, liberação do citocromo c, expressão das proteínas p21, p27, Bax, Bcl-2, ciclina-B1 e NFkB, empregando-se técnicas de marcação específicas para cada ensaio. Os dados foram analisados pelo teste t e a diferença entre as médias dos grupos controle e tratado foram consideradas estatisticamente significativas quando p<0,05. Em relação à linhagem leucêmica K562, o composto LQFM166 foi citotóxico apresentando um perfil dose e tempo dependentes. Foram observadas alterações morfológicas a níveis celular e nuclear, após o tratamento com composto, condizentes com o processo de morte celular por apoptose. Adicionalmente, externalização da fosfatidilserina, aumento da atividade das caspases 3/7, 8 e 9, aumento da expressão das proteínas pró-apoptóticas Bax, p21 e p27, bem como diminuição da expressão das proteínas Bcl-2 e ciclina-B1, após tratamento com a CI50 por 48 horas, desencadeou alterações celulares e moleculares que reforçam a sugestão de processo de morte celular por apoptose. Observouse ainda aumento da liberação do citocromo-c e da expressão da proteína NFkB. Já em relação ao perfil de segurança, o composto mostrou-se relativamente seletivo e com menor toxicidade, uma vez que a CI50 encontrada para a linhagem basal (185,3 μM) foi cerca de duas vezes maior ao encontrado para a linhagem tumoral para o mesmo tempo de exposição (56,76 μM). Considerando os resultados obtidos, pode-se concluir que o composto LQFM166 foi citotóxico sobre a linhagem leucêmica K562, desencadeando alterações morfológicas e bioquímicas características de morte celular por apoptose.
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Siqueira, Junior Jarbas Mota. "Atividade antitumoral da dihidrocucurbitacina B, um composto isolado de Wilbrandia ebracteata Cogn." Florianópolis, SC, 2007. http://repositorio.ufsc.br/xmlui/handle/123456789/90158.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-graduação em FarmacologiaMade available in DSpace on 2012-10-23T06:42:58Z (GMT). No. of bitstreams: 1 247927.pdf: 8834158 bytes, checksum: c3e72e9ec789411c05b1fa2447c78080 (MD5)
A proposta para este trabalho foi investigar as propriedades antitumorais de um composto isolado de WE, a dihidrocucurbitacina B (DHCB), sobre células de melanoma murino B16F10. Nos ensaios do MTT e incorporação de timidina triciada para investigar a viabilidade e proliferação celular, os resultados demonstraram que tanto a fração diclorometânica de WE (WEDC) quanto DHCB reduzem de maneira significativa a proliferação sem alterações marcantes na viabilidade das células B16F10 em cultura, porém DHCB foi menos citotóxica. O mesmo perfil não foi observado em células de fibroblasto murino NIH3T3, onde DHCB promoveu efeito apenas nas maiores concentrações. Antiinflamatórios não esteroidais (Indometacina e Naproxeno) exibiram efeito inibitório sobre a viabilidade e proliferação de células B16F10 apenas em concentrações mais elevadas. Além disso, células B16F10 não expressaram COX-2 nas condições avaliadas. Este fato direcionou nosso estudo para a investigação do efeito da DHCB sobre eventos relacionados à proliferação celular. Análises da expressão de proteínas que participam no controle do ciclo celular revelaram que DHCB foi capaz de reduzir a expressão de ciclina A e principalmente ciclina B1. Ensaios de citometria de fluxo para observar as fases do ciclo celular demonstraram que DHCB promoveu um atraso na progressão do ciclo celular, acumulando as células na fase G2/M, este fato foi acompanhado pelo surgimento de células poliplóides. Ainda por citometria de fluxo, foi observado que DHCB não induz apoptose no ensaio de incorporação de Anexina V-FITC. O surgimento de células poliplóides foi confirmado por imunofluorescência e demonstrou ainda que DHCB promove importantes alterações na distribuição dos filamentos de actina, bem como, nos pontos de adesão focal, concentrando-os. Nos experimentos in vivo, a administração de DHCB por via oral foi capaz de reduzir ambos, o crescimento tumoral e a formação de metástase em pulmão induzidos pela inoculação de células B16F10 em camundongos. Nossos resultados revelam que DHCB reduz a taxa proliferação das células B16F10 devido, pelo menos em parte, à diminuição da expressão de ciclinas, principalmente ciclina B1 e ao dano na distribuição e/ou formação do citoesqueleto de actina, inibindo com isso a citocinese, mas não a cariocinese. Além disso, DHCB foi efetiva quando administrada por via oral em camundongos e não foram observados efeitos adversos como sangramentos, diarréia ou outra alteração comportamental. De maneira geral, nossos resultados sugerem que DHCB apresenta potenciais perspectivas para utilização na terapia de combate ao câncer.
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Rocha, Nubia Ferreira. "Atividade antioxidante e antitumoral em extratos de Jatropha curcas L." Instituto de Ciências da Saúde, Universidade Federal da Bahia, 2013. http://repositorio.ufba.br/ri/handle/ri/20873.
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Submitted by ROBERTO PAULO CORREIA DE ARAÚJO (ppgorgsistem@ufba.br) on 2016-10-18T15:50:18Z
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O pinhão manso (Jatropha curcas L.) é uma planta versátil que ultimamente tem sido utilizada como opção em diversas áreas e na medicina popular. Estudos demonstram seu potencial para o tratamento de constipação, doenças parasitárias, como antimicrobiano, antifúngico, antiinflamatório, analgésico, antipirético, antiviral, antioxidante e atividade contra algumas linhagens tumorais. Dentre os diversos fatores extrínsecos e intrínsecos apontados como responsáveis para o surgimento do câncer, um dos mais discutidos atualmente têm sido os radicais livres ou espécies reativas de oxigênio (ERO), moléculas instáveis, quimicamente reativos produzidos ao longo do metabolismo celular normal, no entanto, podem causar estresse oxidativo que tem sido descrito como um dos principais precursores de doenças como aterosclerose, catarata, doenças neurodegenerativas em especial o câncer. Antioxidantes são moléculas que têm como propriedade o bloqueio, a inibição ou o retardo da deterioração oxidativa, reduzindo ação de radicais livres. O arsenal terapêutico antineoplásico atualmente disponível não são específicos levando à morte de células cancerígenas, como de células normais desencadeando o aparecimento dos efeitos colaterais. Assim, novos compostos que apresentem seletividade são requeridos e recentemente foram introduzidos quimioterápicos de origem natural no tratamento do câncer, o que valida à busca de novos alvos farmacológicos a partir de produtos naturais, principalmente, direcionado às plantas usadas na medicina popular. Nesse contexto, este estudo objetivou avaliar o perfil fitoquímico, a atividade antioxidante e a ação antitumoral de extratos etanólicos de Jatropha curcas L., sob linhagem tumoral in vitro. Para tanto, foram preparados extratos frescos e secos de raiz, caule, folha e sementes por dois métodos de extração (maceração e uso de Soxhlet), foi então realizada a identificação dos grupos fitoquímicos e a triagem destes extratos através do efeito antiproliferativo sob a linhagem HepG2. Para avaliação da atividade antioxidante foram realizadas análises através dos métodos de sequestro do radical livre 2,2-difenil-1- picrilhidrazil (DPPH) e sequestro do radical livre 2,2′-Azino-bis (3-etilbenzotiazolina-6-ácido sulfônico) (ABTS). Os extratos de forma geral apresentaram a presença de flavonoides, taninos catéquicos e fenóis simples. Os rendimentos dos extratos obtidos por ambas as metodologias de extração mostraram diferenças significativas em termos de percentual. O rendimento dos extratos obtidos pelo método de soxhlet apresentou de forma geral menor percentual em relação ao rendimento dos extratos obtidos por maceração, variando entre 1,24 a 24, 96 %, e não tendo relação direta com a atividade antioxidante do extrato. Verificou-se que o extrato preparado com soxhlet de amostras secas de folha de J. curcas apresentou melhor atividade antioxidante atingindo o percentual superior a 80%, quando avaliado pelo método do DPPH enquanto que os extratos obtidos por maceração de sementes frescas (98,54%) e por soxhlet de sementes secas (97,69%) apresentaram melhor capacidade antioxidante usando o método do ABTS. O extrato de folhas secas obtido por soxhlet apresentou atividade antioxidante pelo método do DPPH de 83,1% / EC50 - 47,46 μg/mL,enquanto que o extrato obtido por maceração de folhas frescas foi de 68,1% / EC50 – 52,88 μg/mL, correspondendo aos menores valores de EC50 dos extratos brutos avaliados pelo método do DPPH. Os extratos etanólicos secos de raiz, caule e folhas obtidos por soxhlet, apresentaram melhor efeito antitumoral sobre as células tumorais da linhagem HepG2 e não foram citotóxicos quando avaliados em macrófagos peritoneias. Conclui-se que extratos etanólicos brutos de folhas de Jatropha curcas L. possui atividade antioxidantee extratos etanólicos de raiz e caule promovem efeito antiproliferativo em células tumorais da linhagem HepG2. Conclui-se que a atividade antintumoral sob linhagem HepG2 e antioxidante dos extratos etanólicos de Jatropha curcas L. avaliada através do método de sequestro do radical DPPH e do ensaio ABTS varia em função do método de preparo do extrato, das amostras utilizadas (peso úmido e peso seco) e das partes botânicas analisadas. Este trabalho confirma o potencial antioxidante e antitumoral de extratos etanólicos de Jatropha curcas L.
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Grau, Valls Laura. "Disseny, síntesi i avaluació biològica de nous compostos potencialment antitumorals per inhibició enzimàtica." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/405895.
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Aquesta tesis doctoral està enfocada a la investigació de nous agents amb potencial activitat antitumoral, mitjançant la inhibició d'enzims claus per al desenvolupament i la progressió del càncer, com per exemple KRAS. De la mateixa manera, es busca la preparació de compostos que actuïn sobre més d'una diana i de forma selectiva contra les cèl·lules canceroses per tal de millorar l'eficàcia dels furuts tractaments i els seus efectes adversos. S'ha dut a terme la preparació sintètica de tres sèries de compostos; la primera conté en la seva estructura els nuclis de diarilèter i diarilurea. La segona pren com a model el nucli del polifenol natural resveratrol, sobre el qual es fan modificacions estructurals, tant en els fenols com en el doble enllaç mitjançant la fixació de la configuració desitjada. Finalment, la tercera sèrie es basa en la preparació d'anàlegs de la combretastatina A4 mitjançant modificacions en els dos anells aromàtics i la fixació de la seva configuració mitjançant la introducció d'un cicle. Els compostos s'han preparat utilitzant reaccions clàssiques de química orgànica i posteriorment purificats mitjançant tècniques de separació (cromatografia o recristal·lització) i s'ha dut a terme l'elucidació estructural corresponent. Finalment, s'ha realitzat l'avaluació biològica d'un dels compostos preparats, així com també d'altres caps de sèrie del nostre grup de treball, utilitzant assajos in vitro de viabilitat cel·lular en cèl·lules HT29 de càncer de colon mitjançant la tècnica del MTT. Per tal d'estudiar l'activitat antiproliferativa dels compostos en models in vitro representatius de l'ambient tumoral, s'han utilitzat cultius monocapa en condicions de normòxia i hipòxia, així com també models 3D com els esferoids.This PhD is focused on the discovery of new compounds with potential antitumour activity, through the inhibition of enzymes that are essential in cancer development and progression, like KRAS. At the same time, compounds that exert their activity upon more than one target and selectively in cancer cells are of interest in order to improve treatment efficacy and diminish its side effects. Synthetic preparation of three new series of compounds has been carried out; the first one contains the core of a diarylether and diarylurea. The second takes as a model the scaffold from the natural polyphenol resveratrol, in which structural modifications are done in the phenol moieties and the double bond in order to fix the desired configuration. Finally, the third series is based in the preparation of combretastatin A4 analogues through modification in the two aromatic rings and the fixation of the configuration with the introduction of a cycle. Compounds have been prepared using classical organic chemistry reactions and further purification with separation techniques (chromatography or recrystallization). The consequent structural elucidation has also been performed. Finally, part of the biological evaluation of one of the compounds prepared, as well as other important leads from our group, has been carried out using in vitro assays based on cellular viability in colon cancer HT29 cells using the MTT technique. In order to study the antiproliferative activity of the different compounds in representative models of the tumour environment, monolayer cell cultures have been employed under normoxic and hypoxic conditions as well as 3D models like spheroids.
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Spindola, Humberto Moreira. "Atividade antinociceptiva e antitumoral de compostos isolados da Pterodon pubescens Benth. (Leguminosae- papilionoidea)." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288226.
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Orientadores: Mary Ann Foglio, João Ernesto de CarvalhoTese (doutorado) - Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba
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Resumo: A espécie vegetal Pterodon pubescens Benth tem seu uso amplamente difundido na medicina popular. Neste trabalho, demonstramos de forma específica a atividade antinociceptiva (analgésica) e antitumoral de compostos isolados da espécie. Os resultados mais expressivos foram: 1) fracionamento, isolamento e identificação de compostos biomonitorados por ensaios experimentais in vitro e in vivo; 2) identificação dos compostos 6?-acetoxi-7?-hidroxivouacapano (inédito), éster 6?,7?-diidroxivouacapano-17?-oato de metila e 6?,7?-diidroxivouacapano- 17?-metilenol com atividade antitumoral in vitro específica para uma linhagem celular de próstata (PC-3); 3) biodisponibilidade dos compostos geranilgeraniol e ?ter 6?,7?-diidroxivouacapano-17?-oato de metila com atividade antitumoral através de ensaios in vivo; 4) mecanismos de modulação analgésica dos compostos geranilgeraniol e éster 6?,7?-diidroxivouacapano-17?-oato de metila atribuídos a dor inflamatória, dor neurogênica, receptores gluatamatérgicos, receptores vanilóides, e possível exclusão de receptores opióides; 5) ação antialodínica e anti-hiperalgésica dos compostos geranilgeraniol e éster 6?,7?- diidroxivouacapano-17?-oato de metila, que demonstraram atividade medular e central; 6) mecanismos da ação antinociceptiva relacionados síntese e/ou liberação de serotonina (5-HT) para o composto éster 6?,7?-diidroxivouacapano- 17?-oato de metila e especificidade por receptores serotonérgicos 5-HT3 e imidazólicos I1 para o composto geranilgeraniol. Os resultados apresentados no presente trabalho permitiram determinar a eficácia dos compostos relacionada à atividades analgésica e antitumoral.
Abstract: Pterodon pubescens Benth. species is widespread used in folk medicine. In this study, we demonstrated the antinociceptive (analgesic) and anti-tumor activity of compounds isolated from species. The most relevant results were: 1) bioactivityguided fractionation, isolation and identification of compounds using in vitro and in vivo assays; 2) identification of compounds 6?-acetoxy-7?-hydroxyvouacapan; 6?,7?-dihydroxyvouacapan-17?-oate methyl ester and 6?,7?-dihydroxyvouacapan-17?-metilenol with selectivity for prostate cell line (PC-3); 3) bioavailability of compounds geranylgeraniol and 6?,7?-dihydroxyvouacapan-17?-oate methyl ester with antitumor activity confirmed by in vivo assays; 4) analgesic modulation mechanisms of compounds geranylgeraniol and 6?,7?-dihydroxyvouacapan-17?-oate methyl ester related to inflammatory pain, neurogenic pain, glutamate receptors, vanilloid receptors, and possible exclusion of opioid receptors, 5) antiallodynic and anti-hyperalgesic activities of compounds geranylgeraniol and 6?,7?-dihydroxyvouacapan-17?-oate methyl ester demonstrating spinal and central activity; 6) the antinociceptive mechanisms related to the synthesis and / or release of serotonin (5-HT) for compound 6?,7?-dihydroxyvouacapan-17?-oate methyl ester, and specificity for serotonergic 5-HT3 and imidazoline I1 receptors for geranylgeraniol . The results presented in this study allowed us to determine the efficacy of compounds related to analgesic and anti-tumor activities, with potential for development as drugs.
Doutorado
Farmacologia, Anestesiologia e Terapeutica
Doutor em Odontologia
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Romano, Luis Henrique. "Estabelecimento de meios de cultura para o cultivo de Streptomyces isolados de sedimento marinho." Universidade Federal de São Carlos, 2009. https://repositorio.ufscar.br/handle/ufscar/6955.
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Previous issue date: 2009-10-16Universidade Federal de Sao Carlos
Microorganisms represent an important source for production of bioactive metabolites for diverse applications. The production of these substances is directly related to the culture medium associated with sources of carbon and nitrogen available. Thus this study aimed to establish an appropriate composition of culture media for growth of Streptomyces carpaticus, Streptomyces acrimycini and Streptomyces cebimarensis. These microorganisms were isolated from marine sediments that were preserved in cryovials stored at-80ºC. The species studied were grown on solid media ISP4, ISP5 and GYM and phenotypically characterized. It was observed that Streptomyces carpaticus developed uniformly in all culture media and presented production of pigment in Gym medium. Microorganisms were also grown in solid media (Gym, A1RDP, ISP4 and ISP5). It was observed that Gym is the best medium to promote the microorganism growth. The strains were grown in different concentrations on osmotic medium Gym and on minimal medium with different sources of carbon and nitrogen in crops with flasks. The three strains were grown in batch bioreactors using conventional Gym medium and it was obtained 4 g / L of cell mass of S. carpaticus and S. acrymicini and 6 g / L of cell mass of S. cebimarensis. It was observed the presence of substances with cytotoxic activity on the breeding grounds. Besides, it was observed that the three species probably present diauxic behavior. S. carpaticus consumed preferentially maltose, while other species used glucose first.
Os microrganismos representam uma fonte importante para produção de metabólitos bioativos com diversas aplicações. A produção destas substâncias está diretamente relacionada aos meios de cultura associados às fontes de carbono e nitrogênio disponíveis. Desta forma o presente trabalho teve como objetivo estabelecer uma composição adequada de meios de cultura para o crescimento de Streptomyces carpaticus, Streptomyces acrimycini e Streptomyces cebimarensis isolados de sedimento marinho que foram preservadas em criotubos acondicionados a 80oC. As espécies estudadas foram cultivadas nos meios sólidos ISP4, ISP5 e GYM e caracterizadas fenotipicamente em que salienta-se o Streptomyces carpaticus que desenvolveu-se de forma homogênea em todos os meios de cultivo e apresentou produção de pigmento em meio Gym. As também foram cultivadas em meios sólidos (Gym, A1RDP, ISP4 e ISP5), sendo o melhor meio para crescimento o Gym, as linhagens foram cultivadas em diferentes concentrações osmóticas em meio Gym e em meio mínimo com diferentes fontes de carbono e nitrogênio em cultivos com frascos agitados. As três linhagens foram cultivadas em batelada utilizando-se biorreatores convencionais com meio Gym e obteve-se em termos de massa celular 4 g/L para S. carpaticus e S. acrymicini e 6 g/L para S. cebimarensis. Observou-se também a presença de substâncias com atividade citotóxica nos caldos de cultivo. Observou-se que as três espécies apresentavam comportamento possivelmente diáuxico. S. carpaticus consumiu maltose preferencialmente, diferindo das outras espécies que utilizam primeiramente glicose.
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Ourhzif, El-Mahdi. "Synthèse et évaluation pharmacologique de composés originaux de la famille des méthoxynaphtalènes et lignanes arylnaphtalènes à visée antitumorale." Electronic Thesis or Diss., Université Clermont Auvergne (2021-...), 2022. http://www.theses.fr/2022UCFAC016.
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Le cancer du sein est la tumeur maligne la plus fréquente chez les femmes, il reste le premier en termes d’incidence (2,1 millions de nouveaux cas dans le monde en 2018) et de phénomènes de résistance des cellules cancéreuses aux différents traitements sont apparue. En raison de son impact majeur sur la population, cette maladie représente un problème de santé publique critique qui nécessite des recherches supplémentaires aux niveaux moléculaires afin de définir son traitement spécifique. Le règne végétal reste une source primordiale pour de nombreux chercheurs afin de trouver de nouvelles molécules biologiquement actives, pouvant amener à la découverte de principes actifs potentiellement intéressants sur le plan thérapeutique. Les principes actifs sont directement isolés des extraits des plantes, ou obtenus par hémisynthèse à partir des molécules d’extraction. C’est dans cette démarche que les travaux réalisés par notre groupe de recherche, dans le domaine de l’extraction et la synthèse de substances antalgiques et anticancéreuses, à partir des plantes utilisées dans la pharmacopée traditionnelle, nous ont conduits à envisager des pharmacomodulations en série sur des analogues de la « Guieranone A », molécule naturelle isolée à partir des feuilles de Guiera senegalensis plante largement utilisée en médecine traditionnelle africaine pour ces propriétés thérapeutiques et qui possède des activités antiprolifératives remarquables sur différents lignées tumorales et en particulier sur le cancer du sein (lignée hormono-dépendante MCF-7, CI50 =3,42 ±0,090 µM ). Nous avons donc développé une approche synthétique permettant la préparation des méthoxynaphtalènes et de méthoxynaphtoquinones. Cette approche utilise comme produit de départ le 3,4-diméthoxy benzaldehyde et met en jeu des réactions de type Stobbe et Wittig-Horner-Emmons. Les réactions de synthèses développées sur cette base, ainsi que les molécules préparées, ont permis de synthétiser également des lignanes et des aza-lignanes, composés d’intérêt biologiques ou / et pharmacologiques très représentés dans de nombreuses plantes aromatiques et médicinales (PAM), du genre Justicia et Vitex. Notre méthode de synthèse a permis la préparation avec de bons rendements, des produits naturels et ses analogues (Justicidine C, Cilinaphthalide B, Méthoxy-vitedoamine A), via une réaction de chloroformylaion suivie d’une réaction de couplage de Suzuki-MiyauraBreast cancer is the most common malignant tumor in women, and the first in terms of incidence (2.1 million new cases worldwide in 2018). An increasing problem is the resistance of some cancer cells to different treatments. Due to its major impact on the population, this disease represents a critical public health problem that requires additional research at the molecular level in order to define specific therapies. The plant kingdom remains an essential source for many researchers in order to find new biologically active molecules, which can lead to the discovery of active ingredients. It is in this approach that the work carried out by our research group, in the field of the extraction and synthesis of analgesic and anticancer substances from plants used in traditional pharmacopoeia, led us to consider serial pharmacomodulations on analogues of « Guieranone A », a natural molecule isolated from the leaves of the Guiera senegalensis plant which is widely used in traditional African medicine for its therapeutic properties and which has remarkable antiproliferative activities on various tumor lines and in particular on breast cancer (MCF-7 hormone-dependent line, IC50 = 3.42 ± 0.090 µM). We have therefore developed a synthetic approach using 3,4-dimethoxy benzaldehyde as a starting material and involving Stobbe and Wittig-Horner-Emmons reactions. The synthetic reactions developed on this basis, as well as the molecules prepared, have opened a synthetic route to lignans and aza-lignans, compounds of biological and / or pharmacological interest well represented in many aromatic and medicinal plants (AMP), of the genus Justicia and Vitex. By this way, Justicidin C, Cilinaphthalide B, and Methoxy-vitedoamine A were prepared via a chloroformylation reaction followed by a Suzuki-Miyaura coupling reaction
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Rocha, Fillipe Vieira [UNESP]. "Estudo da atividade biológica de compostos de paládio (II)." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/97918.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Quatro complexos mononucleares inéditos de Pd(II) do tipo [PdX2(tdmPz)] {X = Cl - (1), Br - (2); I - (3); SCN- (4); tdmPz = 3,5-dimetil-1-tiocarbamoilpirazol} foram sintetizados. O composto 1 foi formado a partir da substituição da acetonitrila do complexo [PdCl2(MeCN)2] pelo 3,5-dimetil-1-tiocarbamoilpirazol. Os demais compostos foram obtidos através da substituição dos íons cloreto por brometo (2), iodeto (3) e tiocianato (4). Todos os complexos foram isolados, purificados e caracterizados por análise elementar, espectroscopia na região do infravermelho e ressonância magnética nuclear de 1 H e 13 C{ 1 H}. Os dados experimentais sugerem que, em todos os casos, a coordenação do tdmPz ocorreu através do átomo de enxofre do grupo tiocarbamoil e pelo nitrogênio piridínico do anel pirazólico. O comportamento térmico dos compostos foi investigado por termogravimétria (TG) e Análise Térmica Diferencial (DTA). Pela temperatura inicial de decomposição, a estabilidade térmica dos complexos pode ser ordenada da seguinte maneira: 3 < 4 ≡ 2 < 1. O produto final da termodecomposição foi caracterizado como paládio metálico por difração de raios X de pó. Os complexos, o ligante e a cisplatina tiveram sua citotoxicidade investigada, in vitro, pelo método do MTT frente a 3 linhagens de células cancerosas murinas: adenocarcinoma mamário (LM3 e LMM3) e adenocarcinoma pulmonar (LP07), bem como frente a macrófagos peritoneais murinos. Efeitos citotóxicos promissores (in vitro) foram encontrados para o [PdI2(tdmPz)] (3), mostrando valor de IC50 = 24.5 µM frente a linhagem LM3, para [PdBr2(tdmPz)] (2) com IC50 = 28.7 µM frente as células LP07, e para [Pd(SCN)2(tdmPz)] (4) que se mostrou mais seletivo e citotóxico que a cisplatina frente a linhagem LMM3
Four new mononuclear Pd(II) complexes of the type [PdX2(tdmPz)] {X = Cl - (1), Br - (2); I - (3); SCN- (4); tdmPz = 1-thiocarbamoyl-3,5-dimethylpyrazole} have been synthesized. Compound 1 is formed by the displacement of acetonitrile from [PdCl2(CH3CN)2] by the 1- thiocarbamoyl-3,5-dimethylpyrazole. Complex 2, 3 and 4 were readily obtained by metathesis of the chloride from [PdCl2(tdmPz)2] (1) by the bromide, iodide and thiocyanate ions, respectively. Both complexes have been isolated, purified and characterized by means of elemental analysis, IR spectroscopy, 1 H and 13 C{ 1 H}-NMR experiments. The experimental data suggested that in all cases the coordination of the tdmPz takes place through the sulfur atom from the thioamide moiety and the pyridine-like nitrogen from the pyrazolyl ring. The thermal behavior of the complexes 1-4 has been investigated using thermogravimetry (TG) and differential thermal analysis (DTA). From the initial decomposition temperatures, the thermal stability of the complexes can be ordered in the sequence: 3 < 4 ≡ 2 < 1. The final products of the thermal decompositions were characterized as metallic palladium by X-ray powder diffraction. All the complexes and the ligand together with cisplatin have been tested in vitro by MTT assay for their cytotoxicity against three murine cancer cell lines: mammary adenocarcinoma (LM3 and LMM3) and lung adenocarcinoma (LP07) as well towards normal murine peritoneal exsudate cells (PEC). Promising in vitro cytotoxic effect has been found for [PdI2(tdmPz)] (3), showing the IC50 value of 24.5 µM against LM3, for [PdBr2(tdmPz)] (2) with the IC50 value of 28.7 µM against LP07, and [Pd(SCN)2(tdmPz)] (4) which was more selective and cytotoxic than cisplatin against the cell line LMM3
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Abbehausen, Camilla 1979. "Desenvolvimento de compostos de coordenação com atividades antibacterianas e antitumorais, e interações com biomoléculas." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249128.
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Orientadores: Pedro Paulo Corbi, André Luiz Barboza FormigaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: Complexos metálicos inéditos de paládio, platina, ouro e prata com diferentes classes de ligantes foram desenvolvidos. Dentre os ligantes selecionados estão a L-aliina (ali) e a N-acetil-L-cisteína (nac) que compreendem a classe dos aminoácidos, a 2-mercaptotiazolina (mtz), dentro da classe das tiazolidinas, a sulfadoxina (sfx), representante da classe das sulfonamidas, e ligantes N-heterociclos, piridino derivados com diferentes valores de pKa. Complexos de Pd(II) com L-aliina ([Pd(C6H11NO3S)2]), Ag(I) com N-acetil-L-cisteína ([Ag(C5H9NO3S)]), Ag(I) com sulfadoxina ([Ag(C12H13N4O4S)]), Au(I) com 2-mercaptotiazolina ([Au(CN)(C3H5NS2)]) e uma série de complexos trifenilfosfinoouro(I) com ligantes N-heterociclos ([Au(PPh3)L]+) foram sintetizados e caracterizados por um conjunto de análises químicas e espectroscópicas. Estudos in vitro das sua atividades antibacterianas e antitumorais foram também reali-zados. Atividades antibacterianas e antitumorais significativas foram encontradas para o complexo de Pd(II) com ali e o DNA se mostrou um alvo provável. O complexo Au(I) com mtz apresentou atividade antitumoral e antibacteriana bastante expressiva e uma investigação preliminar de seus mecanismos de ação também demonstrou que o DNA não parece ser o alvo destes compostos nas células. Os complexos de Ag(I) com nac e sfx apresentaram atividades antibacterianas significativas sobre cepas Gram-positivas e Gram-negativas. Os ligantes N-heterociclos 4-picolina (pic), 2-amino-4-picolina (NH2pic) e dimetilaminopriridina (DMAP) possuem valores de pKa crescentes, e foram selecionados para investigar o efeito do pKa na atividade biológica de complexos trife-nilfosfinoouro(I) do tipo [Au(PPh3)L]+, onde L = N-heterocíclico. Esta investigação foi realizada por avaliações in vitro de suas atividades antitumorais, além de estudos do acúmulo celular, do bloqueio do ciclo celular e por interações com biomoléculas como o DNA e proteínas dedos de zinco (zinc fingers, ZF). A atividade antitumoral foi expressiva e os estudos de suas interações com os ZF mostraram que a inibição pode ser modulada com a variação do tipo de proteína e do ligante N-heterociclo selecionado
Abstract: Novel palladium, platinum, gold and silver complexes with different classes of ligands were designed. The selected ligands were L-alliin (ali) and N-acetyl-L-cysteine (nac) which are aminoacids, 2-mercaptothiazoline (mtz), which belongs to the class of thiazolidines, sulfadoxine that represents the class of sulfonamides and N-heterocyclic pyridine derivatives, with different values of pKa. Complexes of Pd(II) with L-alliin ([Pd(C6H11NO3S)2]), Ag(I) with N-acetyl-L-cysteine ([Ag(C5H9NO3S)]), Ag(I) with sulfa-doxine ([Ag(C12H13N4O4S)]), Au(I) with 2-mercaptotiazoline [(Au(CN)(C3H5NS2)]) and a series of complexes of triphenylphosphinegold(I) with N-heterocyclic ligands ([Au(PPh3)L]+) were synthesized and characterized by a set of chemical and spectroscopic analyses. Antibacterial and antitumor activities in vitro were also studied. Significant antibacterial and antitumor activities were found for Pd(II) with ali, and the DNA is the probable biological target. The Au(I) with mtz complex presented noteworthy antitumor and antibacterial activities, and preliminary investigations of its biological mechanism showed that, the DNA is probable not a target of this complex in the cells. The silver complexes with nac and sfx presented significant antibacterial activities. The series of N-heterocyclic ligands 4-picoline (pic), 2-amino-4-picoline (NH2pic) and dimethylaminopyridine (DMAP) shows crescent pKa values and they were selected to investigate the pKa effect in the biological activity of the complexes triphenylphosphinegold(I) [Au(PPh3)L]+, which L = N-heterocyclic. This investigation was performed by evaluation of its antitumor activities in vitro, and also by studies of cell uptake, cell cycle arrest and by interactions with biomolecules as DNA and zinc finger proteins (ZF). The antitumor activity was expressive and the studies with ZF showed that the inhibition is dependent of the kind of protein and of the N-heterocyclic ligand
Doutorado
Quimica Inorganica
Doutora em Ciências
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Pham, Minh Hien. "Etudes sur le métabolisme de l'acide flavone-8-acétique (FAA), un composé à visée antivasculaire antitumorale." Paris 5, 2007. http://www.theses.fr/2007PA05P631.
Повний текст джерелаАнотація:
: L’acide flavone-8-acétique (FAA) est très actif sur les tumeurs solides chez la souris, mais n’a pas montré d'effets anticancéreux chez l’homme. Etant donné que le métabolisme de la FAA pourrait être responsable de cette différence d’activité anticancéreuse, nous avons donc étudié son métabolisme chez la souris et l'homme. Nous avons montré que la FAA est métabolisée par des microsomes murins en 6 nouveaux métabolites de phase I. A comparer aux microsomes humains, la FAA est mieux métabolisée par des microsomes murins en terme de nombre et de quantité de métabolites. Plusieurs cytochromes P450 et l’époxyde hydrolase ont été identifiés dans le métabolisme de la FAA in vitro. Plusieurs métabolites ont aussi été identifiés in vivo chez la souris. Des résultats biologiques in vitro des principaux métabolites de la FAA suggèrent que le métabolisme de la FAA pourrait être impliqué dans la différence d’activité anticancéreuse observée entre deux espècesFlavone-8-acetic acid (FAA) was shown to be very active against solid tumours in the mouse, but was not active in man. Because metabolism could be responsible for this interspecies difference, our aim was to compare FAA metabolism in mouse and man. We showed that FAA is metabolized into 6 new metabolites using mouse microsomes. Compared with human microsomes, FAA was a better substrate for mouse microsomes and yielded more metabolites. Several cytochrome P450s and epoxide hydrolase were identified in FAA metabolism in vitro. Several metabolites were also identified in vivo in the mouse. In vitro, biological results of major FAA metabolites suggest that FAA metabolism could be involved in the marked difference in anticancer activity observed between the two species
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Ouassini, Abdelhamid. "Réactivité du P-trichloro N-dichloro phosphoryle monophosphazène Cl2(O)P-N = PC13 : application à la recherche de molécules présentant une activité antitumorale." Lille 1, 1986. http://www.theses.fr/1986LIL10070.
Повний текст джерелаАнотація:
Ce travail concerne l'étude de la réactivité de Cl2(O)P-N = PCl(3) vis-à-vis des amines (pyrrolidine, bischloroéthylamine, putrescine). Toute une série de dérivés ont été caractérisés. Leurs propriétés alkylantes sur les bases puriques et l'ADN, leur cytotoxicité sur des lignées cellulaires in vitro et leur activité antitumorale in vivo chez la souris ont été étudiées. Une synthèse originale de monophosphazènes R-N=PCl3 a été mise au point
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Ahn, Gang. "Conception, synthèse et évaluation du potentiel antitumoral d’indénoisoquinoléine-5,11-diones polyfonctionnalisées." Thesis, Lille 1, 2010. http://www.theses.fr/2010LIL10129/document.
Повний текст джерелаАнотація:
Les topoisomérases de type I et II (Topo I et Topo II) sont des enzymes dont l'activité majeure repose sur le contrôle de la topologie de l’ADN. Enzymes essentielles lors des processus de réplication, elles constituent, de fait, une cible de choix dans le traitement du cancer. Récemment, les indénoisoquinoléinediones (INDOs) ont fait preuve de très bonnes qualités en tant qu’inhibiteurs de nouvelle génération des Topo I/Topo II. Ainsi, deux séries de dérivés, I et II, intégrant des entités ammoniums et permettant ainsi une augmentation de la solubilité comme des interactions électrostatiques avec l’ADN ont été élaborées. Pour ce qui concerne les molécules de la Série I, deux chaînes aminoalkyles ont été connectés sur les positions N6 et sur les centres carbonés C7, C8 ou C9, tandis que les composés de la Série II ont été équipés de motif acide aminé basique (Gly, Lys, His, Arg) en appendice sur la position N6. En Série I, les INDOs substituées en position C8 ont affiché de très bonnes activités biologiques. En Série II, les dérivés comportant le motif Arg et un amide assurant une fonction de connexion, ainsi que ceux pourvus du motif Gly lié ici par une amine ont présenté des facultés d’inhibition de Topo II remarquablesType I and type II topoisomerases (Topo I and Topo II) are enzymes modulating the topological state of DNA. They are essential proteins involved in DNA replication and consequently are valuable targets in cancer. The indenoisoquinolinediones (INDOs) have emerged as new generation Topo I/Topo II inhibitors. In this regard two series of derivatives bearing ammonium entities with the aim of increasing solubility and developing electrostatic interactions with DNA were designed. Two aminoalkyl chains at N6 and at C7, C8 or C9 positions were grafted on Series I compounds, while Series II molecules were equipped with basic amino acid moieties (Gly, Lys, His, Arg) at N6 position. In series I, C8-substituted INDOs showed potent biological activities whereas in Series II, molecules bearing Arg moiety with amide as a connecting group and Gly moiety linked through amine, displayed prominent Topo II inhibition abilities
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Lacherai, Abdellah. "Réactivité du di(dichlorophosphoryl)imide et du polydichlorophosophazène vis-à-vis de la N,N-bis(chloro-2 éthyl)amine : application à la synthèse de molécules présentant une activité antitumorale." Lille 1, 1992. http://www.theses.fr/1992LIL10126.
Повний текст джерелаАнотація:
Le présent travail concerne l'étude de la réactivité du di(dichlorophosphoryl)imide, HN(POCl2)2, vis-à-vis de la N,N-bis(chloro-2 éthyl)amine (bCEA), avec comme objectif la synthèse de molécules présentant une activité antitumorale. Nous avons pu mettre en évidence la formation des dérivés de mono, di et tétrasubstitution, ainsi que l'existence de diastéréoisomères pour les dérivés mono et bismonosubstitués. L'utilisation conjointe de la RMN (31P, 13C, 1H) et de la spectrométrie de masse a permis de montrer l'instabilité du dérivé tétrasubstitué qui se transforme en dérivé O-alkylé avec perte de HCl. Nous avons ensuite étudié les réactions de cosubstitution de HN(POCl2)2 par la bCEA et l'ammoniac d'une part, la bCEA et la glycine éthyl ester (NH2CH2COOEt) d'autre part. Les études spectroscopiques des produits formés montrent dans ce cas l'intervention de réactions de N-alkylation. Tirant parti de l'expérience acquise par le laboratoire dans le domaine des polyorganophosphazènes, nous avons enfin synthétisé et caractérisé un copolymère de type [NP(NHCH2COOEt)2-x(N(CH2CH2Cl)2)x]n (x=0,6). L'efficacité antitumorale de cinq composés ou mélanges de composés préparés au cours de ce travail a été évaluée. Cette évaluation a permis de montrer que seul le dérivé ayant conservé la structure d'un agent alkylant bifonctionnel présentait une activité antitumorale
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Foka, Maria. "Interaction d'un composé antitumoral le cis-diamminedichloroplatine (II) avec le génome cellulaire : in vitro et in situ." Paris 6, 1987. http://www.theses.fr/1987PA066166.
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