Dissertations / Theses on the topic 'Antimitotic'
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1
Yuen, Tsz Ying. "Enantioselective total synthesis of the antimitotic agent paecilospirone." Thesis, University of Auckland, 2011. http://hdl.handle.net/2292/10767.
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This thesis describes the first, enantioselective total synthesis of the marine natural product paecilospirone (1). Paecilospirone is a polyketide derived metabolite isolated from the marine fungus Paecilomyces sp. collected off the coast of Yap Island, Federated States of Micronesia. Structural assignment following anticancer bioassay subsequently revealed a novel spiro[chroman-2,1(3H)- isobenzofuran] core where an -hydroxyl group occupies the unusual axial position of the sixmembered tetrahydropyran ring. An efficient and flexible strategy was developed to provide access to the [5,6]-bisbenzannulated spiroacetal in a convergent manner. Three key fragments, bromide 162, aldehyde 120 and ketone 92, were synthesised using readily available starting materials. In particular, ketone 92 was obtained from the chiral pool, thus allowing the facile incorporation of enantioselectivity into the synthesis. The fragments were successfully coupled together using an aryllithiation addition and a diasteresoselective, anti-boron aldol reaction. Initial attempts at the late stage spiroacetalisation reaction focused on the acid-mediated cyclisation of MOM-protected ketone 112. However, upon spirocyclisation, 113 readily underwent elimination to afford the corresponding dehydrated products. The problem was exacerbated by the axial orientation of the oxygenated group positioned to the spirocentre and anti to a vicinal hydrogen atom, thus a revision in protecting group strategy was enforced whereby access to the spiroacetal core was envisioned using pH neutral conditions. Attention therefore focused on the model study of a dihydroxyketone equivalent (123) in which the alcohol groups were protected as allyl ethers. Accordingly, treatment of 123 with Pd(PPh3)4 in the presence of a range of silane addictives successfully furnished the desired spiroacetal 124, clearly demonstrating the synthetic utility of this method for the preparation of sensitive spiroacetal systems. Subjection of bis-allyl ketone 166 to the established reaction conditions ultimately led to the completion of the total synthesis of paecilospirone 1.Whole document restricted until Jan. 2014, but available by request, use the feedback form to request access.
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Findlay, A. D. "Total synthesis and structural assignment of antimitotic polyketides." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599022.
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The first part of this dissertation describes the revised stereochemical assignment of the cytotoxic marine macrolide dolastain 19, isolated from the sea hare Dolabella auricularia, which was proposed and subsequently validated by completion of the first total synthesis. Based upon molecular modelling and common biogenetic considerations, four of the twelve stereocentres of the originally proposed structure 50 were inverted in configuration. The carbon backbone 56 of this stereochemically reassigned 14-membered macrolide 54 was assembled using an asymmetric vinylogous Mukaiyama aldol reaction, in combination with boron aldol methodology. A Mukaiyama glycosylation was employed to append the required L-rhamose-derived sugar unit 44. Overall the synthesis was completed in 23 steps and 1.7% overall yield. The second part of this dissertation focuses on the myxobacterium-derived natural product, spirangien A (124). Initial work centred on the preparation of an advanced diene degradation fragment 134, and the subsequent assignment of absolute configuration. The use of a common stereotetrad intermediate 149 was crucial in the development of a convergent and step-economic synthetic strategy. Two series of reactions were performed to access 234 and 148, before recombination via aldol coupling. Elaboration of linear spiroacetalisation precursor 244 provided synthetic spirangien diene 134. Measurement of the optical rotation and comparison with available literature data for natural 134 then enabled the confident assignment of the complete stereochemistry of spirangien A. Laterally, studies focussed on the extension of this synthetic strategy to enable the completion of the total synthesis of spirangien A.
3
Healy, M. "Studies towards the C1-C17 fragment of the potent antimitotic spongistatin 1." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603922.
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This thesis is divided into 7 chapters. Chapter 1 describes the history of the spongistatin family. The isolation of the spongistatins, cinachyrolide and the altohyrtins is reviewed. The structural assignments of these molecules is then discussed and their common identities highlighted. A discussion of the biological properties of the spongistatins then follows before summarising the structural features of the molecules and the issues they pose towards a total synthesis. The spiroketal fragments of the spongistatins are then examined more closely. Spiroketal containing natural products and synthetic methods towards spiroketals are then reviewed. Chapter 2 reviews the synthetic work which has been conducted towards the total synthesis of the spongistatins, paying attention to the 4 groups who have so far completed a total synthesis of one of the spongistatin molecules. Chapter 3 is a review of the strategy our group has taken towards the total synthesis of spongistatin 1. The synthesis of major fragments is described and synthetic problems that have been encountered and have led to a change in the strategy towards the AB spiroketal containing, C1-C17 fragment of spongistatin 1. Chapter 4 outlines the new strategy towards the C1-C17 fragment of spongistatin 1. Synthesis of the C8-C17 fragment is described in detail, with particular attention paid to functionalisation of the C13 alkene via a Wacker oxidation, Shapiro reaction and higher-order cuprate addition to a C12 epoxide. Coupling of a C8 aldehyde with an anomeric phosphonium salt is discussed, and the need for another change is strategy is outlined. Chapters 5 describes the new route to the AB spiroketal via a 1,3-diketone. Synthesis of this fragment is described, and modifications made due to protecting group issues are described in detail, culminating in the successful synthesis of the AB spiroketal. An exciting unified approach to the AB and CD spiroketals is then summarised in Chapter 6.
4
Hodgkinson, Julie L. "The effect of ligands on the assembly of tubulin polymers." Thesis, Liverpool John Moores University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292340.
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Genovino, Julien. "Studies towards the total synthesis of (+)-spirastrellolide A." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608940.
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Shojania, Feizabadi Mitra. "Physical Concepts of Copolymerization of Microtubules in the Presence of Anti-mitotic Agents." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/27795.
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A mathematical approach to the concepts of copolymerization of microtubules in the presence of anti-mitotic drugs is presented in this work. A general feature of the mathematical equations is presented. The possibility of having analytical steady state solutions of dynamic equations is investigated. The structure of equations is narrowed down for the specific brand of anti-mitotic drug, colchicine. The behavior of total T-tubulin concentration in the steady state in a regeneration system is investigated and analyzed through the numerical calculations.Ph. D.
7
Wolmarans, Elize. "In vitro induction of the apoptotic intrinsic pathway via a new antimitotic agent." Diss., University of Pretoria, 2014. http://hdl.handle.net/2263/79212.
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Unique, in silico-designed compounds with possible anticancer properties were identified in our laboratory. 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16), with potential carbonic anhydrase IX inhibiting activity, is capable of interfering with microtubule dynamics.
In this study, it was investigated whether ESE-16 is capable of inducing apoptosis in vitro in the esophageal carcinoma SNO cell line via the intrinsic pathway at a concentration of 0.2μM with an exposure time of 24 hours.
Qualitative results were obtained via polarization-optical transmitted light differential interference contrast microscopy, light microscopy, transmission electron microscopy and confocal microscopy. Results showed hallmarks of apoptosis in the ESE-16-treated cells. In addition, data revealed an increase in the number of ESE-16-treated cells blocked in metaphase. Cell death via apoptosis in the ESE-16-treated cells was confirmed by studying the internal ultrastructure of the cells via transmission electron microscopy, while confocal microscopy revealed abnormal spindle formation and condensed chromatin in ESE-16-treated cells, confirming metaphase block.
Quantitative results were obtained via flow cytometry and spectrophotometry. Cell death via apoptosis in ESE-16-treated cells were quantitatively confirmed by cell cycle progression analysis and the Annexin V-FITC apoptosis detection assay. Metaphase block due to ESE-16 exposure was confirmed by demonstrating an increase in cyclin B levels in the ESE-16-treated cells. In addition, flow cytometry and spectrophotometry revealed dissipation of mitochondrial membrane potential, an increase in superoxide levels, changes in the redox status and an increase in cytochrome c levels in the cytosol of the ESE-16-treated cells. Both initiator caspase 9 and effector caspase 3 activities were increased, which demonstrates that ESE-16 causes cell death in a caspase-dependent manner.
This was the first in vitro study conducted to investigate the action mechanism of ESE-16 on an esophageal carcinoma cell line. The results provided valuable information on the action mechanism of this potential anticancer agent. It can be concluded that the novel in silico-designed compound exerts an anti-proliferative effect on the esophageal carcinoma SNO cell line by disrupting microtubule function resulting in metaphase block. This culminates in apoptotic cell death via the intrinsic apoptotic pathway. This research provided cellular targets warranting in vivo assessment of ESE-16’s potential as an anticancer agent.Dissertation (MSc)--University of Pretoria, 2014.
Physiology
MSc
Unrestricted
8
Golebiowska, Katarzyna. "Identification and development of new antimitotic molecules based on the synergistic effect of fragments." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR13167.
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In vivo, les microtubules – les fibres constitutives du cytosquelette – résultent de l’assemblage longitudinal de 13 protofilaments parallèles par addition (ou polymérisation) des hétérodimères constitués de deux sous unités et de la tubuline. Ces sont des polymères dont l’équilibre dynamique avec les monomèrs, est crucial lors de la mitose et la division cellulaire. La perturbation ou le blocage de cette dynamique conduit généralement à la mort cellulaire. Dans le cadre de cette thèse, nous nous sommes intéressés à la découverte de nouveaux composés simples qui conduisent, comme les produits naturels complexes (le Taxol®, les épothilones, l’éleutherobine et le discodermolide) à la stabilisation des microtubules par inhibition de leur dépolymérisation. Pour réaliser notre objectif, nous avons dans un premier temps synthétisé une collection d’acides carboxyliques, fragments dérivés de l’épothilone, l’éleutherobine et d’autres hétérocycles non naturels, ainsi que différentes amines secondaires dans le but de constituer plusieurs librairies d’amides. Pour l’identification rapide des chimiothèques les plus actives nous avons développé et mis au point une stratégie de criblage et plusieurs déconvolutions ont permis d’identifier les structures des composés des mélanges responsables de la stabilisation des microtubules. L’observation d’un effet synergique entre deux molécules nous a permis ensuite d’optimiser la structure des molécules et de développer de nouveaux ligands plus actifs. Parallèlement à ces travaux nous avons également étudié la localisation du site de liaison des taxoides, et donc de nos molécules. Des études préliminaires réalisées avec du TaxAPU, un photoanalogue de Taxol® radiomarqué, et avec des microtubules sous forme cylindriques et sous forme de feuillets de zinc ont montré que les sous unités de la tubuline sont marquées de façon similaire, dans un rapport de 30/70The key fibre components of the cytoskeleton, microtubules, are formed in vivo by the longitudinal assembly of 13 protofilaments via the addition (polymerisation) of heterodimers of α- and β- subunits of tubulin. They are hollow, tubular fibres whereby dynamic equilibrium is crucial for mitosis and cell division. The perturbation or arrest of their assembly/disassembly leads to cell apoptosis. During the course of this thesis, we were interested in the discovery of new, simple compounds via a fragment-based approach, that are similar to more complex, natural products such as Taxol®. These compounds stabilise the microtubules by inhibition of their disassembly. To realise our aim, we have initially synthesised a collection of different carboxylic acids and secondary amines, the fragments derived form epothilone, eleutherobin and other natural heterocycles that were used to build the libraries of amides. In order to evaluate the biological activity of the amide libraries, we have adopted the microtubule disassembly-based screening that allowed rapid identification of the most active library. Several deconvolutions led us to consequently identify the chemical structures of components being responsible for the stabilisation of microtubules. The observation of the synergistic effect between two active molecules led us to improve their chemical structures and to obtain the ligands with enhanced biological activity. In parallel to this work, we have focused on the first photoaffinity labeling studies of zinc-induced tubulin sheets that could potentially allow for the localisation of the taxoids binding site on microtubules. The preliminary results of the photoaffinity labeling of zinc-induced tubulin sheets and microtubules in the cylindrical form with [3H] TaxAPU, the Taxotere® photoanalogue, have showed that the α- and β-subunits of tubulin are labeled in both these forms in approximately the same ratio 30/70
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Zang, Qin. "Towards the total synthesis of peloruside A analogues." Laramie, Wyo. : University of Wyoming, 2008. http://proquest.umi.com/pqdweb?did=1663059931&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Xu, Lin. "Novel G2 cell cycle checkpoint inhibitors and antimitotic agents isolated through two new HTS bioassays." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ61207.pdf.
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Lee, Wing Sze. "Preparation of doubly p-chiral phosphine oxides for asymmetric catalysis /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?CHEM%202003%20LEE.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003.Includes bibliographical references (leaves 135-142). Also available in electronic version. Access restricted to campus users.
12
Nortje, Evangeline. "Evaluation of a strategy based on multi-drug targeting of cancer proteins in breast cancer cell lines." Thesis, University of Pretoria, 2020. http://hdl.handle.net/2263/79629.
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Therapeutic inefficacy of conventional cancer treatment is a particular dilemma associated with metastatic triple negative breast cancer (TNBC), with patients still facing poor prognosis. The design and development of novel anticancer agents specifically targeted to cancer-associated pathways is of therapeutic interest. The rationale is twofold: firstly, targeted therapy overcomes widespread toxicity and adverse effects of conventional chemotherapy due to the selectivity of the treatment modality. Secondly, synergistic combinations of different classes of highly targeted therapies could hold therapeutic promise to overcome resistance by simultaneously circumventing multiple cancer hallmarks. This study evaluates the in vitro antiproliferative activity of six compounds using breast cancer cell lines as experimental model. Five of these compounds are novel, agents designed in silico to selectively target cancer hallmarks via inhibition of specific cancer-associated proteins. The compounds include an antimitotic (STX1972), three variants of bromodomain 4 (BRD4) inhibitors (Bzt-W41, Bzt-W49 and Bzt-W52), an inhibitor of both sirtuin (SIRT) 1 and 2 (W137) and an inhibitor of janus kinases 1 and 2 (Ruxolitinib). The synergism between paired combinations was also explored.
Two breast cancer cell lines, MDA-MB-231 and MCF-7 were used as experimental models. The MDA-MB-231 cell line is oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) negative and is therefore commonly used to model triple negative breast cancer with invasive and metastatic properties. MCF-7 cells are ER and PR positive and represent the hormone-dependent breast cancer model. The endothelial EA.hy926 cell line was used to represent non-cancerous cells. A crystal violet assay was used to determine the half maximal inhibitory concentration (IC50) of the six compounds on the tested cell lines after 48 h exposure. Drug combination studies based on the Chou-Talalay method of paired drug combinations were performed. Effects of treatment on cell morphology was assessed by means of confocal-microscopy. Flow cytometry was used to study the effects on cell cycle progression, apoptosis, autophagy/lysosomal activity, reactive oxygen species (ROS) production, changes in mitochondrial membrane potential (ΔΨm) and the serine 70 phosphorylation status of Bcl-2. Real-time quantitative PCR was used to analyse the effects of the compounds on the mRNA expression levels of p53, c-myc and bcl-2. Quantitative protein expression of c-MYC was analysed by means of enzyme-linked immunosorbent assay.
In vitro screening for antiproliferative activity revealed that the compounds showed cancer-selective cytotoxic effects when compared to the EA.hy926 control cell line. The initial screening identified three compounds for further investigative inclusion, namely the antimitotic (STX1972), the BRD4i (Bzt-W41) and the SIRTi (W137). STX1972 was found to inhibit cell growth in the nanomolar concentration range, whilst the rest of the compounds showed growth inhibition in micromolar concentration ranges. Bzt-W41 showed significant preferential selectivity for the TNBC MDA-MB-231 cell line versus the hormone-dependent MCF-7 cell line, while STX1972 and W137 exhibited only slight differential selectivity. Two combinations (STX + Bzt-W41 and Bzt-W41 + W137) exhibited synergism, whilst the STX + W137 combination exhibited antagonistic interaction. Cell cycle and apoptosis analysis revealed that STX1972 and Bzt-W41, alone and in combination, selectively induced cell cycle arrest and apoptosis in cancer cells. However, the W137 +Bzt-W137 combination did not show preferential targeting of breast cancer cell lines, with apoptosis induced equally or even more so in the control EA.hy926 cell line. STX1972 and Bzt-W41, as well as their paired combination, was further probed in aim of deciphering their individual and combined mode of action.
STX1972, Bzt-W41 as well as the paired combination proved to selectively inhibit cancer targets resulting in several molecular changes, leading to downstream pathway activation which culminates in both apoptotic and autophagy-related cellular demise. The study contributed towards deducing possible hypotheses regarding the mechanistic behaviours of the individual compounds and elucidated their combined effect during dual treatment. Results warrant future studies to further probe the intricate interaction of pathways involved in the synergistic combination of antimitotics and epigenetic regulators as a novel anticancer therapeutic modality.Thesis (PhD)--University of Pretoria, 2020.
Physiology
PhD
Unrestricted
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Lopez, Isabel. "Effects of antimitotic agents on cultured adrenal chromaffin cells : implications for microtubule involvement with adrenal nicotinic receptors /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487776801318513.
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Stander, Xiao Xing. "In vitro signal transduction mechanism exerted by 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-3-ol-17-one in combination with dichloroacetic acid on breast adenocarcinoma (MCF-7) and breast non-tumorigenic (MCF-12A) cells." Thesis, University of Pretoria, 2014. http://hdl.handle.net/2263/43251.
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Most cancer cells rely on aerobic glycolysis to support the mitochondrial oxidative phosphorylation system (OXPHOS). The persistent oxic-anoxic cycle exerts selection pressures which lead to constitutive activation of glycolysis even in the presence of abundant oxygen. Expression of hypoxia-inducible factor 1 (HIF1) increases following hypoxia in neoplastic cells. This leads to the induction of pyruvate dehydrogenase kinase 1 (PDK1). The latter inactivates pyruvate dehydrogenase (PDH) that converts pyruvate to acetyl-coenzyme A for delivery to the tricarboxylic acid cycle (TAC). Dichloroacetic acid (DCA) is an inhibitor of PDK that forces cells into oxidative phosphorylation thereby suppressing cancer growth.
2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-3-ol-17-one (C9), along with a few other 17β-estradiol analogs, are a novel class of in silico-designed inhibitors of microtubule dynamics. These newly designed and synthesized antimitotic compounds induce G2/M arrest and apoptosis by docking to colchicine binding site between α- and β-tubulin. These compounds are 5 to 20 times more potent than their source molecule, 2-methoxyestradiol (2ME). To improve bioavailability C9 has been in silico-modified at carbon positions C2, C3 and C17 compared to 2ME.
The approach to investigate the anticancer potential of the in silico-designed antimitotic C9 in combination with the glycolytic inhibitor DCA in vitro is novel. Human breast carcinoma cell line MCF-7 and non-tumorigenic breast cells MCF-12A were used as an experimental model system.
The present study demonstrated that DCA (7.5 mM) in combination with C9 (130 nM) selectively inhibited half of MCF-7 cells‘ population (50.8%). Under the same treatment conditions, MCF-12A cells displayed high number of cell survival (70% cell growth). Qualitative morphological studies revealed decreased cell density in both cell lines, as well as hallmarks of apoptosis and autophagic processes including formation of apoptotic bodies, DNA fragmentation and autophagic vacuoles. Cell cycle- and apoptosis quantification analyses revealed C9+DCA treatment induced apoptosis in both cell lines and exhibited selectivity towards tumorigenic cells. Presence of autophagosome was observed and microtubule-associated protein 1 light chain 3 (II) (LC3-II) expression was elevated. Reduction of mitochondrial membrane potential depolarization in tumorigenic MCF-7 cells was demonstrated, but not in MCF-12A cells. Oxidative stress tests suggested the combination treatment C9+DCA is able to induce lysosomal rupture and/or mitochondrial damage in tumorigenic MCF-7 cells. Kinase inhibition studies revealed that transient activation of c-Jun N-terminal kinase (JNK) plays an important role in cell proliferation. However, C9+DCA stimulated prolonged JNK activation and, in turn, promoted Bcl-2 phosphorylation, thereby facilitating autophagic and apoptotic cell death.
C9+DCA induced expression of a number of genes related to stress in MCF-7 treated cells including TP53BP1, MDM2 and BBC3/PUMA. Genes related to cell motility and maintenance of the cytoskeleton such as ACTG1, MAP7, TUBA1, TUBA6, TUBA8 and TUBB2A genes were down-regulated. In MCF-12A cells, treatment of C9+DCA induced expression of multidrug resistance gene ABCB1. Moreover, genes involved in reactive oxygen species metabolism FTH1, GSTA2, NOS2A, SMOX, SOD1 and SOD2 were also up-regulated.
In conclusion, the novel 17β-estradiol derivative, C9, in combination with DCA is a potent antiproliferative treatment. This study addressed the mechanisms of combination treatment at the basis of molecular and cellular level, warranting further research projects to develop viable and functional combination treatment as clinically useable anticancer agents.Thesis (PhD)--University of Pretoria, 2014.
lk2014
Physiology
PhD
Unrestricted
15
Herrmann, Jennifer [Verfasser], and Rolf [Akademischer Betreuer] Müller. "Mode-of-Action studies on cytostatic compounds from myxobacteria : antimitotic pretubulysins and actin-targeting chondramides / Jennifer Herrmann. Betreuer: Rolf Müller." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1063134838/34.
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Zarifi, Khosroshahi Mitra, and Khosroshahi Mitra Zarifi. "Study of the hepatic stability and the therapeutic potential of novel antimitotic prodrugs selective for CYP1A1-expressing breast cancer cells." Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/36900.
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Nous avons récemment découvert et étudié une nouvelle classe d'agents antimicrotubules appelés phényl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzènesulfonates (PAIB-SOs) hautement actifs et sélectifs pour les cellules cancéreuses du sein. Leur mécanisme de sélectivité est basé sur la métabolisation des PAIB-SOs par le CYP1A1 en agents antimitotiques puissants appelés phényl 4-(2-oxo-3-imidazolidin-1-yl)benzènesulfonates (PIB-SOs). L'objectif principal de ma recherche était d'évaluer la période nécessaire à l’induction d’une activité cytotoxique significative de quelques-uns de ces PAIB-SOs prometteurs sur les cellules cancéreuses du sein. Dans un second volet, nous désirions étudier la stabilité métabolique et la cinétique de bioactivation par le CYP1A1 de 8 PAIB-SOs phare en vue d’en sélectionner 4 pour des essais sur des animaux. Premièrement, nos études ont montré que l'activité antiproliférative des PAIB-SOs est concentration et temps dépendante. Un temps de contact des PAIB-SOs étudiés avec les cellules cancéreuses du sein variant de 24 à 36 h est nécessaire pour observer une activité antiproliférative significative. Deuxièmement, nous avons confirmé que tous les PAIB-SOs évalués sont rapidement biotransformés en présence de CYP1A1 en PIB-SOs. Troisièmement, les expériences de stabilité hépatique des PAIB-SOs incubés avec des microsomes soit humains, de souris ou de rats ont montré que leur demi-vie et leur clairance intrinsèque varient selon la structure du PAIB-SO et l’espèce animale étudiée. La stabilité des PAIB-SOs incubés avec des microsomes de souris est plus faible que lorsqu’incubé avec des microsomes humains ou de rats. De plus, la stabilité métabolique de ces PAIB-SOs avec les microsomes humains ou de rats est similaire. Le criblage de notre chimiothèque a permis d’identifier les CEU-829, -938, -934 et -913 comme étant les PAIB-SOs métaboliquement les plus stables et générant les plus basses concentrations de PIB-SOs avec des demi-vies respectives de 22, 55, 31 et 41 minutes dans les microsomes humains, de 43, 52, 23 et 44 minutes dans les microsomes de rat et de 3,7, 20, 12 et 1,6 minutes dans les microsomes de souris. Nos études ont également mis en évidence les CEU-934 et -938 comme des molécules candidates prometteuses pour des études de pharmacocinétique et de pharmacodynamie chez la souris et les CEU-829 et -913 chez les rats.Nous avons récemment découvert et étudié une nouvelle classe d'agents antimicrotubules appelés phényl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzènesulfonates (PAIB-SOs) hautement actifs et sélectifs pour les cellules cancéreuses du sein. Leur mécanisme de sélectivité est basé sur la métabolisation des PAIB-SOs par le CYP1A1 en agents antimitotiques puissants appelés phényl 4-(2-oxo-3-imidazolidin-1-yl)benzènesulfonates (PIB-SOs). L'objectif principal de ma recherche était d'évaluer la période nécessaire à l’induction d’une activité cytotoxique significative de quelques-uns de ces PAIB-SOs prometteurs sur les cellules cancéreuses du sein. Dans un second volet, nous désirions étudier la stabilité métabolique et la cinétique de bioactivation par le CYP1A1 de 8 PAIB-SOs phare en vue d’en sélectionner 4 pour des essais sur des animaux. Premièrement, nos études ont montré que l'activité antiproliférative des PAIB-SOs est concentration et temps dépendante. Un temps de contact des PAIB-SOs étudiés avec les cellules cancéreuses du sein variant de 24 à 36 h est nécessaire pour observer une activité antiproliférative significative. Deuxièmement, nous avons confirmé que tous les PAIB-SOs évalués sont rapidement biotransformés en présence de CYP1A1 en PIB-SOs. Troisièmement, les expériences de stabilité hépatique des PAIB-SOs incubés avec des microsomes soit humains, de souris ou de rats ont montré que leur demi-vie et leur clairance intrinsèque varient selon la structure du PAIB-SO et l’espèce animale étudiée. La stabilité des PAIB-SOs incubés avec des microsomes de souris est plus faible que lorsqu’incubé avec des microsomes humains ou de rats. De plus, la stabilité métabolique de ces PAIB-SOs avec les microsomes humains ou de rats est similaire. Le criblage de notre chimiothèque a permis d’identifier les CEU-829, -938, -934 et -913 comme étant les PAIB-SOs métaboliquement les plus stables et générant les plus basses concentrations de PIB-SOs avec des demi-vies respectives de 22, 55, 31 et 41 minutes dans les microsomes humains, de 43, 52, 23 et 44 minutes dans les microsomes de rat et de 3,7, 20, 12 et 1,6 minutes dans les microsomes de souris. Nos études ont également mis en évidence les CEU-934 et -938 comme des molécules candidates prometteuses pour des études de pharmacocinétique et de pharmacodynamie chez la souris et les CEU-829 et -913 chez les rats.
We recently found and studied a new class of antimicrotubule agents named phenyl 4-(2-oxo-3- alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) that are highly active and selective to breast cancer cells. PAIB-SOs are the first antimicrotuble CYP1A1-dependent prodrugs and their mechanism of selectivity is based on the metabolization in human breast cancer cells of PAIB-SOs by CYP1A1 into potent antimitotics named phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). The main objective of my research was to evaluate the period necessary to trigger an efficient antiproliferative activity on breast cancer cells and to study the metabolic stability and the kinetics of activation by CYP1A1 of 8 promising PAIB-SOs exhibiting high antiproliferative activity and selectivity toward breast cancer cells aiming to select 4 PAIB-SOs for animal studies. We first found that the antiproliferative activities of PAIB-SOs are concentration and timedependent. A contact time of the selected PAIB-SOs with breast cancer cells varying from 24 to 36 h is required to observe a significant antiproliferative activity. We also found that all PAIBSOs are rapidly metabolized in the presence of CYP1A1 into PIB-SOs. Finally, the hepatic stability experiments of PAIB-SOs using human, mouse or rat microsomes showed that the halflife and the intrinsic clearance depend on the structure of the PAIB-SO and the animal species studied. The stability of PAIB-SOs in mouse microsomes was weaker than in rat or human microsomes which were equivalent. Our screening program identified CEU-829, -938, -934 and - 913 as our most stable PAIB-SOs and generating the lowest quantity of PIB-SOs when incubated with human and rodent microsomes. In addition, they respectively exhibited half-lives of 22, 55, 31 and 41 minutes in human microsomes, 43, 52, 23 and 44 minutes in rat microsomes and 3.7, 20, 12 and 1.6 minutes in mouse microsomes. Altogether, our studies identified CEU-934 and - 938 as suitable candidates for further pharmacokinetic and pharmacodynamic evaluation in a mouse model and CEU-829 and -913 in a rat model.
We recently found and studied a new class of antimicrotubule agents named phenyl 4-(2-oxo-3- alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) that are highly active and selective to breast cancer cells. PAIB-SOs are the first antimicrotuble CYP1A1-dependent prodrugs and their mechanism of selectivity is based on the metabolization in human breast cancer cells of PAIB-SOs by CYP1A1 into potent antimitotics named phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). The main objective of my research was to evaluate the period necessary to trigger an efficient antiproliferative activity on breast cancer cells and to study the metabolic stability and the kinetics of activation by CYP1A1 of 8 promising PAIB-SOs exhibiting high antiproliferative activity and selectivity toward breast cancer cells aiming to select 4 PAIB-SOs for animal studies. We first found that the antiproliferative activities of PAIB-SOs are concentration and timedependent. A contact time of the selected PAIB-SOs with breast cancer cells varying from 24 to 36 h is required to observe a significant antiproliferative activity. We also found that all PAIBSOs are rapidly metabolized in the presence of CYP1A1 into PIB-SOs. Finally, the hepatic stability experiments of PAIB-SOs using human, mouse or rat microsomes showed that the halflife and the intrinsic clearance depend on the structure of the PAIB-SO and the animal species studied. The stability of PAIB-SOs in mouse microsomes was weaker than in rat or human microsomes which were equivalent. Our screening program identified CEU-829, -938, -934 and - 913 as our most stable PAIB-SOs and generating the lowest quantity of PIB-SOs when incubated with human and rodent microsomes. In addition, they respectively exhibited half-lives of 22, 55, 31 and 41 minutes in human microsomes, 43, 52, 23 and 44 minutes in rat microsomes and 3.7, 20, 12 and 1.6 minutes in mouse microsomes. Altogether, our studies identified CEU-934 and - 938 as suitable candidates for further pharmacokinetic and pharmacodynamic evaluation in a mouse model and CEU-829 and -913 in a rat model.
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Gu, Hyangja. "The effects of antimitotic drugs and mAb35 on ?-tubulin mRNA, microtubules and nicotinic receptor-mediated catecholamine secretion in adrenal chromaffin cells in culture /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487759914759158.
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Ahn, Sunjoo. "Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281966697.
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Paun, Andrea. "Regulator T cells in murine AIDS." University of Western Australia. Microbiology and Immunology Discipline Group, 2005. http://theses.library.uwa.edu.au/adt-WU2005.0115.
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[Truncated abstract] In the last ten years regulator T (Tr) cells have re-emerged as an integral part of the immune system. Research in this field has rapidly demonstrated the role of these cells in the maintenance of immune homeostasis and their involvement in disease. Tr cells are generated in the thymus as a normal part of the developing immune system. Furthermore, antigen-specific Tr cells are induced in the periphery by a mechanism which is yet to be completely elucidated, but is likely to involve dendritic cells. Tr cells play an important role in autoimmune disease, transplantation tolerance, cancer. Most recently Tr cell involvement has been demonstrated in a growing number of infectious diseases. Tr cell induction was reported in Friend Virus infection at the commencement of this study, and subsequent to publication of our findings have also been identified in FIV and HIV. Murine AIDS (MAIDS) is a fatal chronic retroviral infection induced in susceptible strains of mice by infection with BM5d, a replication defective virus, in a viral mixture which is designated LP-BM5. The manipulation of Tr cells detailed in this thesis and the related publication represent the first reported therapy utilising targeted removal of Tr cells. Chapter 1 summarises the literature relevant to this study up to November 2004. Chapter 2 details the materials and methodologies used in this work. Chapter 3 investigates whether Tr cells are involved in the development of murine AIDS, particularly in the early stages of infection. The data presented in this chapter provides evidence of a population of CD4+ Tr cells which express CD25 on their cell surface and secrete TGF-β, some IL-10 and low levels of IL-4 are induced following infection with LP-BM5. These cells were found to arise by day 12 post infection (pi) by flow cytometry and immunosuppressive cytokine expression was found to peak at day 16 pi indicating a role in the early stages of disease progression. Chapter 4 investigates the effect of therapeutically targeting these induced Tr cells using the antimitotic agent Vinblastine during their induction period. The efficacy of treatment was found to be time dependent and was shown to abrogate disease progression maximally when given at day 14 pi. Treatment with anti-CD4 monoclonal antibody was also found to be efficacious at day 14 pi and confirmed the identity of the Tr cells as being CD4+ T cells. Adoptive transfer studies demonstrated that the return of these cells to a successfully treated host results in renewed MAIDS progression, confirming their role in disease progression
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SOUZA, AMANDA de. "Avaliação citotóxica de Amoxilina e Clavulanato de Potássio em mexilhões Perna perna." reponame:Repositório Institucional do IPEN, 2016. http://repositorio.ipen.br:8080/xmlui/handle/123456789/26395.
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Dissertação (Mestrado em Tecnologia Nuclear)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP
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Oliveira, Dalliane Macedo Lopes de. "Efeito antimitótico de um derivado de pirimidinona no desenvolvimento embrionário de ouriços-do-mar." Universidade Federal da Paraíba, 2015. http://tede.biblioteca.ufpb.br:8080/handle/tede/9458.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Cancer is characterized by uncontrolled cell growth of a particular tissue, which invades and impairs healthy cells functions. Chemotherapy is the main cancer treatment, and consists of drug administration that interferes in several metabolic pathways, leading to cancer cell death. Among the main chemotherapy drugs, antimitotics directly affect cell division. This study aimed to investigate the effect of a pyrimidinone derivative (4-4-chloro-phenyl)-2-(-4-methoxy-phenyl)-6-oxo-1,6-dihydropyrimidine- 5-carbonitrile, Py-09) on embryonic development of the sea urchin Echinometra lucunter. Adult animals were collected at João Pessoa coast, Paraíba, Brazil and kept in filtered sea water under constant air flow. Gametes or embryos were treated with Py-09 and the effects of the compound were analyzed on fertilization, embryonic development, mitochondrial membrane potential (ΔΨm), production of reactive oxygen species (ROS) and ABC transporters activity. Py-09 (12.5 μM) inhibited around 60% fertilization of pretreated eggs. However, treatment of sperm with Py-09 did not affect fertilization rate. Treatment of zygotes with Py-09 inhibited the early embryonic development in a time and dose-dependent pattern, with the maximum effect at 50 μM (EC50 = 12.5 μM). Morphological changes were observed in the pattern of embryos cleavage (unequal cleavage) and at larval stages (irregular distribution and cracks of spicules and pigment cells leakage). Py-09 induced the loss of ΔΨm without altering ROS intracellular levels. The assays with ABCB1 and ABCC1 transporters inhibitors (Reversin 205 and MK571, respectively) showed that Py-09 is not ABC proteins substrate. The intracellular calcein accumulation assay and PY-09/vinblastine association demonstrated Py-09 was not able to increase intracellular calcein fluorescence levels and that the compound did not reverse MXR phenomenon. In summary, this study demonstrated that the Py-09 features a remarkable antimitotic activity, producing changes both in morphology and cell physiology. Further studies are needed for a better understanding of the mechanism of action of the compound, and research on the potential of Py-09 as pharmacological tool for in vitro studies, as well as its therapeutic use.
O câncer é caracterizado pelo crescimento descontrolado de células de um determinado tecido, que invadem e comprometem, funcionalmente, células sãs do organismo. A quimioterapia é o principal tratamento do câncer, consistindo na administração de drogas que interferem em diversas vias metabólicas, ocasionando a morte celular. Dentre os principais quimioterápicos, os antimitóticos são drogas que afetam, diretamente, a divisão celular.O presente trabalho teve como objetivo investigar a atividade antimitótica de um derivado de pirimidinona (Py-09) no desenvolvimento embrionário do ouriço-do-mar Echinometra lucunter. Animais adultos foram coletados na costa João Pessoa, Paraíba, Brasil, mantidos em água do mar filtrada sob fluxo de ar constante. Os gametas foram coletados por injeção intracelomática de KCl. Os gametas ou embriões foram tratados com Py-09 e foi analisada a atividade do composto sobre a fertilização, o desenvolvimento embrionário, o potencial de membrana mitocondrial interna (ΔΨm), a produção de espécies reativas de oxigênio (ROS) e a atividade de transportadores ABC. O Py-09 (12,5 μM) inibiu, em cerca de 60%, a fertilização de óvulos previamente tratados com o composto. No entanto, o tratamento dos espermatozoides com o Py-09 não afetou a taxa de fertilização. O tratamento dos zigotos com o Py-09 inibiu o desenvolvimento embrionário inicial, apresentando um efeito antimitótico dose e tempo-dependente, atingindo um efeito máximo na concentração de 50 μM (CE50 = 12,5 μM). Foram observadas alterações morfológicas no padrão de clivagem dos embriões (clivagem desigual) e em estágios larvais (distribuição irregular e fissuras das espículas e extravasamento de células pigmentares).O tratamento com Py-09 promoveu a perda do ΔΨm, sem, entretanto, alterar os níveis intracelulares de ROS. O ensaio com os inibidores dos transportadores ABCB1 e ABCC1 (Reversina 205 e MK571, respectivamente) mostrou que o Py-09 não é substrato de proteínas ABC. Por outro lado, o ensaio de acúmulo intracelular de calceína e os ensaios de associação do Py-09 com a vimblastina demonstraram que o mesmo não reverte o fenômeno MXR, uma vez que o composto não foi capaz de aumentar os níveis de fluorescência intracelular da calceína, e a associação Py-09 (12,5 μM)/vimblastina (100 e 400 nM) apresentou o mesmo efeito inibitório da vimblastina per se.Em suma, o presente trabalho demonstrou que o Py-09 apresenta uma marcante atividade antimitótica, acarretando alterações tanto na morfologia quanto na fisiologia celular.Estudos adicionais são necessários para um maior entendimento do mecanismo de ação do composto, e para a investigação acerca do potencial do Py- 09 como ferramenta farmacológica para estudos in vitro, assim como para o seu uso terapêutico.
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Beck, Daniel Antony Speedie, and beckautomatic@gmail com. "Stereoselective intramolecular Michael addition reactions of pyrrole and their application to natural product syntheses." The Australian National University. Research School of Chemistry, 2006. http://thesis.anu.edu.au./public/adt-ANU20070130.130009.
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Chapter one; (-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis.
¶
Chapter two; Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product.
¶
Chapter three An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi., focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13].
¶
Chapter four Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13:
The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine
[(+)-134].
The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid
(-)-rhazinilam [(-)-1].
The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis.
¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.
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Nguyen, Thi Thanh Binh. "Synthèse, évaluation biologique et vectorisation de dérivés hétérocycliques de la combretastatine A-4." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10306.
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La combretastatine A-4 (CA-4), produit naturel isolé d’un arbuste d’Afrique du sud (Combretum caffrum K.), a montré des propriétés antitumorales intéressantes. Grâce à sa capacité à empêcher la polymérisation de la tubuline, ce stilbénoïde possède des propriétés cytostatiques sélectives à l’égard de différentes lignées cellulaires cancéreuses. Certains dérivés hydrosolubles de la CA-4 comme la CA-4P (fosbretabuline) et le composé AVE8062 (ombrabuline) sont actuellement en essais cliniques pour le traitement de différents cancers. Trois séries de dérivés de la CA-4 ont été synthétisées : les Z-stilbènes, les 1,2- diaryl-1,2-éthanediones et les 5,6-diaryl-2,3-dihydropyrazines. Dans ces composés, le cycle B est remplacé par divers hétérocycliques (indole, benzofurane, benzothiophène, thiophène) attachés à la position C2. Ces dérivés ont été évalués pour leur capacité à inhiber l'assemblage de la tubuline. Le produit Z-stilbènes portant un noyau benzo[b]thiophène a montré une activité antitubuline comparable à celle de la colchicine et de la deoxypodophyllotoxine. L’effet sur l'organisation intracellulaire des microtubules et les propriétés antimitotiques de ce composé ont été ensuite testés sur les lignées cellulaires de kératinocytes SKv-a et HaCaT. Enfin, des essais préliminaires de vectorisation de ce composé dans des nanoparticules lipidiques solides (SLN) ont été réalisésCombretastatin A-4 (CA-4), a natural product first isolated from the South African bush willow tree (Combretum caffrum K.), possesses interesting antitumor properties. Due to its capacity to inhibit tubulin polymerization, this stilbenoid shows selective cytostatic activities against various cancer cell lines. Some water-soluble CA-4 derivatives such as CA-4P (fosbretabuline) and AVE8062 (ombrabuline) are currently undergoing clinical trials for the treatment of various cancers. Three series of CA-4 analogues, Z-stilbenes, 1,2-diaryl-1,2-ethanediones and 5,6-diaryl-2,3-dihydropyrazines, were synthesized. In these compounds, the B ring is replaced by various heterocycles (indole, benzofurane, benzothiophene or thiophene) attached at the C2 position. These derivatives were evaluated for their ability to inhibit tubulin assembly. Compound Z- stilbenes bearing a benzo[b]thiophene ring showed an antitubulin activity comparable to that of colchicine and deoxypodophyllotoxine. Its effect on the intracellular organization of microtubules and antimitotic properties were then tested on two keratinocyte cell lines HaCaT and SKV-a. Finally, preliminary essays to the vectorization of this compound in solid lipid nanoparticles (SLN) were carried out
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VARCA, GUSTAVO H. C. "Desenvolvimento de hidrogel nanoestruturado contendo complexo de papaína e ciclodextrina." reponame:Repositório Institucional do IPEN, 2014. http://repositorio.ipen.br:8080/xmlui/handle/123456789/28051.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A papaína é uma enzima proteolítica empregada no debridamento e cicatrização de feridas. Contudo, problemas de estabilidade na forma farmacêutica, bem como reações alérgicas reportadas por pacientes submetidos à tratamentos com a enzima, culminaram na restrição aos produtos contendo papaína para uso tópico por órgãos regulatórios internacionais. Este trabalho objetivou desenvolver hidrogel nanoestruturado contendo complexo de papaína e ciclodextrina visando obter forma farmacêutica estável e eficaz como curativo dérmico, com redução da resposta imunológica. A síntese do hidrogel foi realizada combinando fenômenos de cristalização e/ou reticulação e esterilização simultânea induzida por radiação gama, de modo a promover nanoestruturação adequada da membrana para veiculação da papaína nativa e do complexo. O complexo e o produto final tiveram suas propriedades biológicas e físico-químicas avaliadas. O hidrogel a base de PVA contendo complexo de papaína-ciclodextrina apresentou características adequadas para aplicação como curativo, além de apresentar indícios de redução na resposta imunológica e melhora na citocompatibilidade quando comparado à papaína nativa, isso devido ao encapsulamento molecular com a ciclodextrina e à alta retenção do complexo por parte da matriz. Por outro lado, a irradiação, não alterou o perfil citotóxico da enzima, mas acarretou leve diminuição em seu potencial imunogênico. O hidrogel se mostrou promissor para uso como curativo e demonstrou potencial redução nas reações adversas desencadeadas pelo uso da papaína.
Tese (Doutorado em Tecnologia Nuclear)
IPEN/T
Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP
FAPESP:10/10935-9
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Lima, Junior Claudio Gabriel. "Investigação da reação de Morita-Baylis-Hillman em reator de micro-ondas usando aldeídos aromáticos e isatina como eletrófilos: avaliação da atividade citotóxica em linhagem de células de leucemia promielocítica humanas (HL-60)." Universidade Federal da Paraíba, 2012. http://tede.biblioteca.ufpb.br:8080/handle/tede/7080.
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Previous issue date: 2012-11-14Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
In this work, we describe the investigation of the Morita-Baylis-Hillman reaction in microwave reactor, under closed vessel conditions to prepare 40 adducts, six novel, using 30 aromatic aldehydes and isatin as electrophiles and acrylonitrile (62a) , methyl acrylate (2), hydroxyethyl acrylate (62b), 2,2-dimethyl-1 ,3-dioxalyl acrylate (62c) and 2,3-dihydroxypropyl acrylate (62d) as Michael acceptors catalyzed by 1, 4-diazabicyclo [2.2.2] octane (DABCO). Most adducts were synthesized efficiently in short reaction times and excellent yields (70-99%) using this reaction protocol. However, this synthetic methodology showed limitations for less reactive substrates due to formation of byproducts and in some cases the formation of the desired adduct was not obtained. The application of low temperatures and / or conventional room temperature protocol led to the adducts preparation in a chemoselective manner. We proved that the formation of 2-hydroxy (4-bromophenyl) methyl acrylate (43) is reversible at 120 ° C, which explains the restriction observed in the preparation of certain adducts using heating by microwave irradiation and successfully protocol employing temperature of 0º C. Preliminary evaluation of cytotoxic activity against cell lines of human leukemia HL-60 was performed, where the nitrilated isatin derivatives adducts (56a and 56b) were the most active. Preliminary studies of antimitotic activity in embryonic cells of sea urchin (Echinometra lucunter) performed with nitrilated adducts containing pyridine rings (49, 47, 20), nitro group (16, 38, 15) and bromine atom attached to the aromatic ring (42) revealed that except 47, all investigated adducts strongly inhibited stages of embryonic development of the first cleavage and morula. Moreover, experimental observations showed no inhibition of microtubule organization, induction of cell necrosis and toxicity of the adducts, suggesting that the blocking mechanism of action of protein synthesis and / or DNA.
Neste trabalho, nós descrevemos a investigação da reação de Morita-Baylis-Hillman em reator de micro-ondas, sob condições de vaso fechado para preparação de 40 adutos, sendo seis inéditos, utilizando 30 aldeídos aromáticos e a isatina como eletrófilos e acrilonitrila (62a), acrilato de metila (2), acrilato de hidroxietila (62b), acrilato de 2,2-dimetil-1,3-dioxalila (62c) e acrilato de 2,3-diidroxipropila (62d) como aceptores de Michael catalisada por 1,4-diazabiciclo [2.2.2] octano (DABCO). A maioria dos adutos foram sintetizados de forma eficiente em curtos tempos reacionais e excelentes rendimentos (70-99%) usando este protocolo reacional. No entanto, esta metodologia sintética apresentou limitações para substratos menos reativos, devido a formação de subprodutos e em alguns casos a não formação do aduto desejado. A aplicação de baixa temperatura e / ou protocolo convencional a temperatura ambiente conduziram a preparação dos adutos de forma quimiosseletiva. Provamos que a reação de formação do acrilato de 2-hidroxi(4bromofenil)metila (43) é reversível a 120° C, fato que explica a limitação observada na preparação de alguns adutos usando aquecimento por irradiação de micro-ondas e o sucesso no emprego de protocolo a temperatura de 0º C. A avaliação preliminar da atividade citotóxica contra linhagem de células de leucemia humana HL-60 foi realizada, onde os adutos nitrilados derivados da isatina (56a e 56b) foram os mais ativos. Estudos preliminares da atividade antimitótica em células embrionárias de ouriço do mar (Echinometra lucunter) realizados com adutos nitrilados contendo anéis piridínicos (49, 47, 20), grupo nitro (16, 38, 15) e átomo de bromo ligados ao anel aromático (42) revelaram que, exceto 47, todos os adutos investigados inibiram fortemente os estágios de desenvolvimento embrionário de primeira clivagem e mórula. Além disso, observações experimentais não demonstraram inibição da organização dos microtúbulos, indução de necrose celular e toxicidade por parte dos adutos, sugerindo como mecanismo de ação o bloqueio da síntese protéica e/ou de DNA.
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Dutheil, Sophie. "Une nouvelle zone de neurogenèse réactionnelle et fonctionnelle chez le mammifère adulte : les noyaux vestibulaires - mise en évidence et implication fonctionnelle dans différents modèles de déafférentation vestibulaire." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4752/document.
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Seules deux structures du système nerveux central adulte, la zone sous-granulaire et la zone sous-ventriculaire, produisent continuellement de nouveaux neurones et sont considérées comme neurogènes. En dehors de ces zones délimitées, le tissu nerveux ne possède pas de telles facultés. Leurs influences anti-neurogènes peuvent cependant être mises entre parenthèses dans certaines conditions. Cela se produit après neurectomie vestibulaire unilatérale (NVU) chez le chat adulte ; en effet, des études immunohistochimiques et comportementales nous ont permis de découvrir l'existence d'une neurogenèse réactionnelle de type GABAergique dans les noyaux vestibulaires désafférentés situés dans le tronc cérébral. Nos résultats témoignent de l'implication fonctionnelle de cette prolifération cellulaire dans la restauration des fonctions posturo-locomotrices suite à une NVU. Nous avons également mis en évidence que les caractéristiques et l'intensité de la désafférentation vestibulaire déterminent, non seulement, le décours temporel de la restauration des fonctions vestibulaires, mais aussi les différents mécanismes cellulaires post-lésionnels et le potentiel neurogène des noyaux vestibulaires. En outre, nous avons démontré que l'activation ou le blocage des récepteurs GABA de type A influence d'une part, les différentes étapes de la neurogenèse réactionnelle dans les noyaux vestibulaires, et détermine d'autre part le décours de la récupération comportementale des animaux. Ainsi, le système GABAergique joue-t-il un rôle important dans la régulation de la neurogenèse induite après NVU et de sa fonctionnalitéOnly two structures of the adult central nervous system: the subgranular zone and the subventricular zone, produce continuously new neurons and are considered as neurogenic. Outside these two delimited areas, nervous tissue does not have such faculties. The anti-neurogenic influences can however be removed under specific conditions. That is what happens after unilateral vestibular neurectomy (UVN) in the adult cat: behavioral and immunohistochemical studies have demonstrated the existence of a reactive GABAergic neurogenesis in the deafferented vestibular nuclei located in the brainstem. Our results demonstrate the functional role of the vestibular cell proliferation in the postural locomotor function recovery after UVN. We also demonstrated that characteristics and intensity of the vestibular lesion, not only determine the time course of recovery of vestibular function, but also the post-lesional cellular mechanisms and the neurogenic potential occurring in the vestibular nuclei. In addition, we showed that activation or blockade of GABA type A receptors influences the different steps of neurogenesis in the vestibular nuclei, and also determines the time course of behavioral recovery. Thus, the GABAergic system influences reactive neurogenesis that is benefic for vestibular compensation process. Finally, the results of a recent study demonstrated that vestibular-hippocampal relations exist, and that stress induced by vestibular deafferentation can modulate adult neurogenesis in both the vestibular nuclei and the dentate gyrus in the adult cat
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Kamech, Nedia. "Regulation de la proliferation des cellules de mammiferes : effet d'agents interagissant directement : vinblastine, colchicine, griseofulvine, taxol; ou indirectement : ampc, concanavaline a, butyrate; sur le cytosquelette des fibroblastes normaux." Paris 6, 1987. http://www.theses.fr/1987PA066175.
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Li-Ying, Su, and 蘇麗瑛. "Synthesis of Potential Bioreductive and Antimitotic Anticancer Agents." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/09700099662539513584.
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碩士國防醫學院
藥學研究所
93
ABSTRACT 1 Solid tumour causes cells with deficiency oxygen to form hypoxic cell because the blood is insufficient in supply. Cancer patients who resist to chemotherapy and radiotherapy to cause, while causing and treating solid tumour, curative effect is not good. The bioreductive anticancer agents is one kind of novel anticancer drugs, which the selectivity acts on hypoxic cell.Dual actions of bioreductive anticancer agents directly destroy DNA and act as auxiliary treatment for chemotherapy / radiotherapy. At present, the bioreductive anticancer agents can be divided into four main classes in accordance with the structure. Among them it is the highest with the cytotoxic selectivity (HCR=300) of cell to hypoxic cell of tirapazamine (TPZ) of aromatic N-oxides,which the side effect is minimum.The bioreductive agents lead development potentiality of novel anticancer agents Regard TPZ as the lead compound of anticancer agents in this laboratory synthesis and modification based on TPZ. We aimed at synthesis a series of di-N-oxide chemicals to develop higher selectivity effects and lower toxicity targeting hypoxic cells. The target compounds assess were examined the cytotoxic activity by SRB assay. Those target compounds have no significant anticancer effect, but compound 13a, 15, 24b, 24c, showed slightly better cytotoxic effect than lead compound TPZ (compound 3 ). ABSTRACT 2 Mitotic is cellular process of differentiation. It can produce with the daughter cell of the same self-characteristics of master cell. So the growth of the life and growth in nature cancer cells can make use of those characteristics. One of that antimitotic agents the pharmaceutical and acted on the cell had antimitotic effect and reach the anticancer result. The mechanism are : 1. Inhibiting the assembly of tubulin; 2. Stabilising microtubule and to prevent it to depolymerization. (example: Taxol) At present, clinical use antimitotic agents amost originate from active constituents of natural plants. Regarding podophyllotoxin as the lead compound of antimitotic anticancer agents were in progress in our laboratory. A rapid one-pot microwave synthetic approach, target compounds 4a-l were synthesized for examining antineoplastic activity. The target compounds assess were examined the cytotoxic activity by SRB assay. Those target compounds have no significant anticancer effect.
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Fang, Yang Ming, and 楊明芳. "2-Amino and 2’-Aminocombretastatins Derivatives as Potent Antimitotic Agents." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/56495780464339932541.
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碩士臺北醫學大學
藥學系
94
A novel series of 2-amino and 2’-aminocombretastatins derivatives was synthesized and evaluated for antitumor activity. Several compounds had excellent antiproliferative activity as inhibitors of tubulin polymerization. Compound 1, 11, and 12 with IC50 of 1.6, 1.7, and 1.8 M, respectively, exhibited more potent inhibition of tubulin polymerization than colchicine and approximately as active as CA4. They also displayed antiproliferative activity with an IC50 values ranging from 11 to 44 nM in a variety of human cancer cell lines from different organs. SAR information indicates that the amine substituent at 2-position of ring A or ring B in combretastatin moiety plays an important role in the activity of this series of compounds.
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Engers, Darren William. "Studies directed towards the total synthesis of (+)-peloruside A." Thesis, 2006. http://hdl.handle.net/2152/2530.
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Zhang, Xin. "Synthesis of Furo[2,3-d]Pyrimidines, Thieno[2,3-d]Pyrimidines, Pyrrolo[2,3-d]Pyrimidines as Classical and Nonclassical Antifolates, Receptor Tyrosine Kinase (RTK) Inhibitors and Antimitotic Agents." 2012. http://digital.library.duq.edu/u?/etd,154127.
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An introduction, background and research progress in the areas of antifolates, receptor tyrosine kinase (RTK) inhbitors and antimitotic agents has been discussed.
<br>Thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFTase) are important folate dependent enzymes that are targets for cancer chemotherapy and the treatment of infectious diseases. Classical antifolates, in most cases, are substrates for folypoly-g-glutamate synthase (FPGS) and rely on folate transporter systems to enter cells. As a part of this study, twenty-eight compounds were designed on the basis of existing clinically active compounds and crystal structures, synthesized and evaluated as single and/or muliple targeted classical and nonclassical antifolates to decrease toxicity and improve the activity and selectivity of existing therapeutic agents. In addition, these structures provides an extension to the structure activity relationship in the antifolate area.
<br>RTK inhibitors and antimitotic agents are important antitumor agents and are extensively used in the clinic for the treament of various types of cancers. Pgp overexpression is one of the common reasons for drug resistance to existing antitumor agents and consequently the reason for some chemotherapeutic failures. A furo[2,3-d]pyrimidine compound was discovered to have dual RTK inhibitory activity along with antimitotic activity that circumvent pgp over expression. Antimitotic activity via the binding at the colchicine site is one of the mechanisms of action. Molecular modelling and biological evaluation suggest the importance of conformational restriction for activity. Fifty-seven furo[2,3-d]pyrimidines and six thieno[2,3-d]pyrimidines were designed on the basis of crustal structures and synthesized as potential RTK inhibitors with antimitotic antitumor activity. Four pyrrolo[2,3-d]pyrimidines were designed and synthesized as antimitotic anticancer agents that also reverse pgp action.Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences
Medicinal Chemistry
PhD
Dissertation
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Yoo, Hye-Dong. "Bioactive secondary metabolites from marine algae and study of oxidized anandamide derivatives." Thesis, 1997. http://hdl.handle.net/1957/33639.
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My investigations of the natural products of marine algae have resulted in
the discovery of several new secondary metabolites. Bioassay-guided
fractionation led to the isolation of these new compounds and spectroscopic
analysis was utilized in their structural characterization.
Two new and potent antimitotic metabolites, curacins B and C, were
isolated from a Curacao collection of Lyngbya majuscula. In addition, four
curacin A analogs were prepared by semisynthetic methods. The structures of
the new curacins and the curacin A analogs were determined by spectroscopic
analysis in comparison with curacin A. The biological properties of the new
natural products and synthetic derivatives of curacin A were examined.
Investigations of another Curacao collection of L. majuscula revealed a
new cytotoxic lipopeptide, microcolin C. Microcolin C was found to have an
interesting profile of cytotoxicity to human cancer-derived cell lines.
A new metabolite, vidalenolone, was isolated from an Indonesian red
alga Vidalia sp. The structure of this new cyclopentenolone-containing
compound was determined by a combination of spectroscopic methods.
Filamentous cells isolated from female gametophytes of the brown alga
Laminaria saccharina were cultured in flasks or bioreactors. These cultures
produced a variety of w6-lipoxygenase metabolites: 13-hydroxy-9,11-octadecadienoic acid (13-HODE), 13-hydroxy-6,9,11,15-octadecatetraenoic acid (13-HODTA), and 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE).
Five oxidized anandamide derivatives were prepared from anandamide through autoxidation in an exploration of ligand binding to the cannabinoid receptor. Their structures were determined by a combination of NMR spectroscopy and GC-MS. The cannabinoid receptor binding affinity of these derivatives was evaluated. This study revealed the following trend in activity: anandamide > 15- > 9- > 8- > 11- > 5-hydroxyanandamide.Graduation date: 1998
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Burgett, Anthony W. G. "Synthesis and molecular pharmacology of the diazonamides." 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=209.
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Radhakrishna, P. M. "Studies in the synthesis and antimitotic activity of Aza and other analogues of Beta-Apopicropodophyllin." Thesis, 1990. http://hdl.handle.net/2009/2551.
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Xu, Lin. "Novel G2 cell cycle checkpoint inhibitors and antimitotic agents isolated through two new HTS bioassays." Thesis, 2000. http://hdl.handle.net/2429/13485.
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The search for new pharmacologically active agents by screening natural sources such as microbial fermentations and plant extracts has led to the discovery of many clinically useful drugs that play a major role in the treatment of human diseases. Analogous to the investigation of terrestrial products, some recent studies of marine natural products have focused on their potential applications, particularly the treatment of human diseases, such as cancer. The goal of my thesis research was to discover structurally novel G2 cell cycle checkpoint inhibitors and antimitotic agents in natural product extracts. Active crude extracts were identified via high throughput bioassays for G2 checkpoint inhibitors and antimitotic agents. The assays were developed by our collaborator Michel Roberge and the details of the assays are introduced in the thesis. Several G2 checkpoint inhibitors were isolated and identified from extracts of marine organisms and plants. A new inhibitor pachyclavularolide F (18) was isolated from the soft coral Pachyclavularia violacea. Several inactive analogs including pachyclavulariolides A (43), B (44), C (45), D (46), E (47), and G (48) were also isolated from P. violacea. The previous known inhibitor staurosporine (10) and its new semisynthetic oxazolidone derivative (17) were discovered from a marine microorganism. The known metabolites aaptamine (12), isolated from the sponge Aaptos auberitoides and the diterpene lactones (19, 54, 55) from the tropical bush Parinari curatellifolia were found to show the G2 checkpoint inhibition. Using Dr. Roberge's high throughput antimitotic assay, the paclitaxel derivatives 10-deacetyltaxuyunnanine A (71) and 7-(β-xylosyl)-10-deacetyltaxol C (72) were isolated from the Southern American plant Ilex macrophylla. This work resulted in the discover of a new natural source for paclitaxel derivatives, and it also validated the accuracy and efficiency of the new antimitotic assay. My research on new metabolites from a marine sponge Xestospongia ingens guided by a traditional cytotoxicity bioassay led to several new ingenamine alkaloid derivatives, including ingenamines H (56), I (57), J (58), K (59), and L (60).
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Liu, Yu-Ching, and 劉玉晴. "Synthesis of FIT-OH and AVLPR-OH analogs as cell differentiation agents and antimitotic agents." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/58720361787781287995.
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碩士中國醫藥學院
藥物化學研究所
89
As part of our continuing search for potential cell differentiation agents, AVLPR-OH was selected as the lead compound for structural modification. On the other hand, a series of FIT-OH analogs was designed as antimitotic agents by Molecular Modeling. The target compounds were synthesized on Fmoc-Amino acid-Wang resin for peptide acids (TP-1, TP-3 — TP-11 and PP-1), and Rink resin for peptide amides (TP-2, PP-2 and PP- 3), by standard Solid Phase Peptide Synthesis. Each of synthesized products were purified by RP-HPLC and their molecular weight were confirmed by FAB-MS.
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Kim, Tae-Seong. "Synthetic studies on natural products : Part I. The total synthesis of ��-euonyminol and ��-3,4-dideoxymaytol : Part II. The absolute configuration and enantioselective synthesis of curacin A." Thesis, 1996. http://hdl.handle.net/1957/34376.
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CHUNG, HSIU-CHANG, and 鍾秀昌. "Screening of Antimitotic Drug Combretastatin-A4 Derivatives That Are Capable of Inducing Autophagy in Neuroblastoma SHSY5Y Cell Line." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/85613922388269018056.
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碩士國立中山大學
生物科學系研究所
102
Autophagy is a process to clear unwanted protein aggregates and damaged organelles for recycling cellular resources. It is a critical mechanism to maintain cellular homeostasis for cellular survival when facing environmental stress. Therefore, aberrant autophagy might lead to the diseases such as cancer, pathogen infection and neurodegenerative diseases. Autophagic proecess depends on the fusion of autophagosome with lysosome for the enzymatic degradation of its content. Previous reports indicated the involvement of microtubule in mediating the fusion of autophagosome with either lysosome or late endosome. Therefore, proper dynamic for microtubule formation is critical for autophagic process. Combretastatin A-4 (CA-4) is a useful nature product exhibits anticancer and anti-angiogenesis activity by targeting microtubule formation. However, its clinical use is limited as it exhibits drawbacks such as high toxicity and low water solubility. To improve its clinical use, efforts are ongoing in synthesizing better CA-4 derivatives as anticancer drug candidates. A series of Combretastatin A-4 (CA-4) enediyne derivatives were synthesized by Professor Ming-Jung Wu in the Department of Chemistry of National Sun Yat-Sen University. In this thesis, research was focusing on the analyzing their effects on the microtubule formation in neuroblastoma SHSY5Y and hepatoma Hep3B cell lines by confocal microscopic analysis. The results showed that like CA-4, among 9 enediyne derivatives analyzed, LO-OMe、LO-NH2、LO-py and HYH10f could inhibit microtubule formation using dosage of their individual IC50. The results of flow cytometric cell cycle analysis showed that LO-OMe、LO-NH2 and HYH10f also had antimitotic effect in that they caused G2/M arrest of SHSY5Y cells. Whereas, the derivatives CPC14c, CPC20a, CPC15a, CPC19a and HYH10a had no effects on microtubule formation or cell cycle arrest. These results indicated the modification or replacement of different function groups might affect their activities differentially. We further investigated the effects of these CA-4 enediyne derivatives on the autophagic process by monitoring the level of two autophagic marker proteins LC3-II and p62 using western blot analysis. Our results showed that like CA-4, LO-OMe, LO-NH2 and CPC15a could lead to the increase of both LC3-II and p62. Compound HYH10f could increase LC3-II level, but not on the level of p62. The rest of the derivative compounds had no effects on the level of both LC3-II and p62. Our results again showed that functional modification might affects autophagic process differentially. The detail signaling mediating their effects on autophagy awaits further investigation. Understanding the molecular mechanism underlies might be helpful in evaluation of their use as therapeutic agents for cancer or neurodegenerative diseases.
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Martins, Nuno Miguel Martins. "Fluorescent and radionuclide labeling of a synthetic neuroactive glycoside." Master's thesis, 2012. http://hdl.handle.net/10451/9168.
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Tese de mestrado em Química (Química, Saúde e Nutrição), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012Clinically brain and spinal cord injuries are very serious. These injuries can result in permanent, transient sensory or motor defects resulting in serious individual consequences besides social and economic ones. Currently, it is estimated that 90 million people around the world suffer from spinal cord injury (SCI). One of the main obstacles to central nervous system (CNC) trauma repair is the formation in the lesion area of a growth inhibitory cellular-molecular structure, called “glial scar”. This inhibitory environment in the injured spinal cord blocks axon growth and precludes nerve repair. We have previously reported that the new glucoside 3 is a potent inhibitor of glioma and melanoma cells growth. It inhibited human melanoma (A-375 cells) division with an ID50 below the micromolar range (0.6 +- 0.3 µM). Thereafter, 3 was found as potential useful in the treatment of SCIs. Considering the potencial application of glucoside 3 for SCI repair, there is a great interest to understand its biological behavior. Aiming to such goal, were designed new 3 derivatives containing molecular probes (fluorophore/radionuclide) suitable for conventional molecular imaging techniques. This work describes the synthesis, characterization and in vitro biological evaluation of a fluorescent label (NBD) 3 derivative. Primary cultures of astrocytes, from postnatal rats (day 0 -1), were treated with NBD-3 derivative at final concentrations of 3, 15 and 30 µM. Fluorescence microscopy images, obtained after 24 h of treatment, demonstrated the ability of NBD-3 derivative to permeate through the astrocyte cell membrane. Also, the number of astrocytes decreased as the concentration of the synthetic inhibitor increase, showing similar antimitotic activity as the original glucoside 3. The establishment of a synthetic approach to prepare fluorinated-23 derivative is also reported. This approach will be adopted for the synthesis/radiosynthesis of a fluorine label (19F/18F) 3 derivative. We also plan to perform biodistribution studies with the 18 F-3 derivative. We also plan to perform biodistribution studies with the 18F-3 derivative, in order to assess its in vivo tissue distribution/brain uptake.
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Hsu, Tsang-Yi, and 許滄沂. "The effect of cultural factors on the production of flavonoids in antimitotic agents treated Belamcanda chinensis(L.)DC adventitious roots." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/95882930820065700464.
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Vaz, Sara Marisa Duarte. "Age-dependent sensitivity to antimitotics: the role of FOXM1 and its therapeutic potential." Tese, 2021. https://hdl.handle.net/10216/135863.
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Vaz, Sara Marisa Duarte. "Age-dependent sensitivity to antimitotics: the role of FOXM1 and its therapeutic potential." Doctoral thesis, 2021. https://hdl.handle.net/10216/135863.
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Lo, Yu-Hsiang, and 羅宇翔. "Design and Synthesis of Novel Enediynes and Their Derivatives as Antimitosis Agents." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/26238457985717201947.
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博士高雄醫學大學
藥學研究所
97
This dissertation is composed of three parts; first, we designed a new series of enediyne and their derivatives and evaluated for their growth inhibition activity against human tumor cell lines. We have found a lot of compounds that displayed potent growth inhibition of cancer cell, such as compound 2-(6-(2-trifluoromethylphenyl)-3(Z)-hexen-1,5-diynyl)aniline (37c). According to the mechanism assay, these compounds, displayed a significant G2/M phase arrest via microtubules depolymerization and induced apoptotic progress. Second, we coupled 2-(6-(2-trifluoromethylphenyl)-3(Z)-hexen-1,5-diynyl)aniline (37c) with the DNA alkylating agent to give a hybrid agent and evaluated its bio-activity. Third, we use 2-(6-(2-trifluoromethylphenyl)-3(Z)-hexen-1,5-diynyl)aniline (37c) as a lead compound and we found that bio-activity of 2-(6-(2-anilinyl)-3(Z)-hexen-1,5-diynyl)-1,2,3-trimethoxy benzene (51) is more potent than compound 2-(6-(2-trifluoromethylphenyl)-3(Z)-hexen-1,5-diynyl)aniline (37c).
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Tseng, Chen-Yi, and 曾貞宜. "Design and Synthesis of Enediyne containing Combretastatin A-4 Analogues as Antimitosis Agents." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/87317551054580236019.
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碩士國立中山大學
化學系研究所
98
We designed a new series of enediyne and their derivatives, and evaluating for their growth inhibition activity against human tumor cell lines. This dissertation is composed of two parts. First, compounds 6c, 6e, 6g and 7g displayed good growth inhibition activity against A549 (non-small-cell lung cancer), AGS (human stomach adenocarcinoma), PC-3 (prostate cancer), BT483 (breast carcinomas), HeLa (human cervical epithelioid carcinoma), OVCA (ovarian cancer cell line), SKHep (hepatocellular carcinoma), H460 (human lung cancer cell line) and SW620 (Human Colorectal Cancer Cell Line), especially compound 7g is better, and its average IC50 is 8.79μM. Second, compounds 25a and 26 displayed better growth inhibition activity against HeLa (human cervical epithelioid carcinoma), OVCA (ovarian cancer cell line), AGS (human stomach adenocarcinoma) and H460 (human lung cancer cell line), and their average IC50 are10.82 and 11.08 μM.
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Teesdale-Spittle, P. H., Klaus Pors, R. Brown, Laurence H. Patterson, and J. A. Plumb. "Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells." 2005. http://hdl.handle.net/10454/3191.
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NoA novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/ cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.