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1
Apps, MIchael Garry. "Platinum anticancer drugs and drug delivery systems". Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14409.
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In this thesis two different ways to improve platinum-based chemotherapy were investigated. The first was through the use of a new slow release clay-based drug delivery vehicle and the second through the design and synthesis of novel dinuclear platinum complexes. For the clay-based drug delivery research, the platinum anticancer complex [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] chloride, PHENSS, was loaded into montmorillonite (MMT) clay. The PHENSS was found to be incompletely burst released from the MMT. The MMT also had a negative effect on the in vitro cytotoxicity of PHENSS in the human breast cancer cell lines MCF-7 and MDA-MB-231. Overall the results demonstrate that MMT is not a suitable slow release vehicle for PHENSS. For the dinuclear platinum complex synthesis research, new bispyridine-based bridging ligands were synthesised using an amide coupling reaction. The bridging ligands were then reacted with transplatin to yield the dinuclear platinum complexes. The platinum complexes have potential application as anticancer agents and the synthetic method can be modified to produce other multinuclear complexes.
2
Kozlowska, Hanna. "Interaction of dexrazoxane with anticancer drugs". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0001/MQ32158.pdf.
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Tao, Zhimin. "Analysis of cytotoxicity of anticancer drugs". Related electronic resource:, 2007. http://proquest.umi.com/pqdweb?did=1407688361&sid=4&Fmt=2&clientId=3739&RQT=309&VName=PQD.
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Liu, Tong. "The synthesis of novel anticancer drugs". Thesis, University of Glasgow, 2003. http://theses.gla.ac.uk/4464/.
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Our studies on the synthesis and biological evaluation of novel anticancer drugs consist of three research areas; namely, synthesis of Mitogen Activated Protein (MAP) kinase inhibitors, Checkpoint (Chk1) inhibitors and nordihydroguaiaretic acid (NDGA) analogues. The first research area involved synthesis of MAP kinase inhibitors. MAP kinases are a family of serine I and threonine II kinases which can act together to generate a process of phosphorylation events within the cell signalling pathway leading eventually to cell division. The compounds made in this project were specifically designed to target the stress related kinases, a MAP kinase pathway which controls the expression of genes involved in cell proliferation. The stress related kinases are known to have serine or threonine joined to a proline III residue. In an attempt to prepare selective inhibitors of stress related kinases, compounds of types IV and V were deigned in which a conformationally restricted serine analogue is joined to L-proline via an amide link in one of two possible ways. Examples of these two sets of compounds were synthesised and those that were tested by Professor David Gillespie at the Beatson Institute for Cancer Research, Glasgow were shown not to be inhibitors of these kinases. (Fig. 1144A) The second research area concentrated on the checkpoint signalling pathway. Components in the DNA damage checkpoint signalling pathway such as ChK1 could be potential targets for chemical intervention. Caffeine VI and pentoxifylline VII have been shown to sensitise p53-deficient tumour cells to killing by DNA damage. We envisaged that the xanthine derivatives, caffeine VI and pentoxifylline VII might also disrupt the G2 checkpoint by preventing activation of Chk1. To test his hypothesis, a range of xanthine derivatives shown below were prepared by alkylation of theophylline VIII or theobromine IX. (Fig. 1144B) The biological evaluation of these xanthine derivatives by Professor Gillespie revealed that three of these compounds, X, XI and XII, suppressed G2/M arrest very effectively. All three active compounds possess a long aliphatic chain that provides a large degree of flexibility to the structures. The long aliphatic chains could bind to a hydrophobic pocket in the enzyme’s active site that might confer selectivity on the compounds. (Fig. 1144C) The third area, synthesis of NDGA analogues, was the major part of the synthetic work. NDGA XIII is known to be a selective inhibitor of lipoxygenase and blocks small cell lung cancer growth in vitro and in vivo. In addition to its lipoxygenase activity, NDGA was demonstrated to inhibit c-kit, a tyrosine kinase that has been observed preferentially in SCLC. The main drawbacks to the use of NDGA in cancer treatment are its poor solubility and moderate potency. Therefore chemical modifications are required to provide better compounds for clinical use. Preliminary work in our group was performed by McDonald and Macleod. They synthesised a range of analogues of NDGA which were tested for their activity in vitro by Professor Michael Seckl at the Medical Oncology Department of Hammersmith Hospital, London. Improved potency over NDGA for new analogues with 4-6 atoms between the two aromatic rings was observed. Furthermore introduction of an amide linkage between the two aromatic residues resulted in NDGA analogues which are more active than NDGA. Based on these preliminary results, the structural modifications proposed for this project focused on three areas. The main programme of research was drug solubilisation of new analogues which have higher potency than NDGA for in vivo work. The second area of study sought to introduce position variations of the amide linkage between the two aromatic residues. The third area of work involved modification of the substituents on the two aromatic rings. (Fig. 1144D) A range of NDGA analogues was successfully synthesised and evaluated for anticancer activity in vitro. Compounds XIV and XV were confirmed as lead compounds which are ten times more active than NDGA. Compound XIV was successfully transformed into a water soluble form XVI which is now available for in vivo work. In addition NDGA was converted into a water soluble form which was more potent than NDGA in vitro. Moreover a NDGA analogue XVII with no free hydroxy groups was found to be as active as NDGA, which was an unexpected discovery. (Fig. 1144E)
5
Song, Di. "Bladder tissue pharmacokinetics of anticancer drugs /". The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487940308433249.
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Ratcliffe, Andrew J. "Synthesis of non-mutagenic anticancer drugs". Thesis, University of Bath, 1987. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378598.
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Pettersson, Hanna Ilse. "Quinolinequinones as anticancer agents". Thesis, University of Exeter, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249038.
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Wang, Shining. "DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS". Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/2535.
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PharmaceuticsPh.D.
EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG] dimension to any pharmacokinetic [PK] and pharmacodynamic [PD] analysis. The goal of this project was to characterize the PK/PD properties of gefitinib in tumors and then apply these results to design rational drug design regimens, and provide a foundation for future studies with EGFR inhibitors. Progressions of in vitro and in vivo studies were completed to understand the PK and PD behavior of gefitinib. In vitro cytotoxicity assays were first conducted to confirm the gefitinib sensitivity differences in a pair of human glioblastoma cell lines, LN229-wild-type EGFR and LN229-EGFRvIII mutant, an EGFR inhibitor-sensitizing mutation. Subsequent in vitro PD studies identified phosphorylated-ERK1/2 (pERK) as a common PD marker for both cell lines. To describe the most salient features of drug disposition and dynamics in the tumor, groups of mice bearing either subcutaneous LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors were administered gefitinib at doses of 10 mg/kg intravenously (IV), 50 mg/kg intraarterially (IA) and 150 mg/kg orally (PO). In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral pERK. Hybrid physiologically-based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration-profile, a tumor compartment depicting drug disposition in the tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type, yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. Based on the designed PK/PD equivalent dosing regimens for each tumor type, gefitinib 150 mg/kg PO qd × 15 days and 65 mg/kg PO qd × 15 days multiple-dose studies were conducted in wild-type EGFR and EGFRvIII mutant tumor groups, respectively. In each tumor group, gefitinib plasma and tumor concentrations were measured on both day 1 and day 15, as were tumoral amounts of pERK. Different from single-dose model simulations, gefitinib showed nonlinear PK property in the wild-type tumor due to the down-regulation of membrane transporter ABCG2. Moreover, acquired resistance of tumoral pERK inhibition was observed in both tumor types. Nevertheless, gefitinib had an analogous growth suppression action in both tumor groups, supporting the equivalent PD dosing strategy. Overall, single-dose gefitinib PK/PD investigations in a pair of genetically distinct glioblastomas facilitated the development of hybrid physiologically-based PK/PD models for each tumor type, and further introduced a novel concept of PK/PD equivalent dosing regimens which could be applied in novel drug development paradigms. Preliminary multiple-dose gefitinib studies revealed more complex PK/PD characteristics that needed to be further explored.
Temple University--Theses
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Leczkowska, Anna. "Non-covalent DNA-binding ruthenium anticancer drugs". Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1695/.
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The research work described in this thesis concerns metal-based anticancer drugs with an emphasis on non-covalent DNA-binding supramolecular assemblies. The project involves the preparation of a series of mono- and bi-metallic ruthenium complexes with a primary focus on fluorescent dinuclear triple-stranded helicates with different structural topographies. Emphasis is then directed towards an investigation of the DNA binding characteristics of these molecules and an evaluation of their anticancer properties in human cancer cell lines. Attention is brought to the significance that the cylinder-building moieties and their structural characteristics have to these features. The studies also include an examination of the effects of chirality of the investigated supramolecular systems and the impact they have on molecular recognition. This is addressed via studies of the interaction of optical isomers of ruthenium triple-stranded helicates with DNA as a biomolecular target system and with Δ-TRISPHAT as a representative small chiral molecule.
10
Yarema, Kevin J. (Kevin Jon). "Cellular responses to platinum-based anticancer drugs". Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/33495.
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Matkar, Smita S. "Mechanism of action of potential anticancer drugs". Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/2368.
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Traditionally, inoperable or metastatic cancers have been treated by causing massive DNA damage in order to induce self-destruction (apoptosis) of the rapidly multiplying cancer cells. Initially, this strategy works for many cancers, in particular those which express normal p53 tumor suppressor protein. However, most cancers eventually aquire mutations in either p53 or other signaling molecules and fail to initiate apoptosis in response to severe DNA damage. During this study three types of compounds were investigated for their DNA damaging and anticancer effects: a pair of novel metal containing compounds, a pair of natural products, and a known synthetic drug which had been used many years ago for completely different indication. It was shown that all stop the growth of cancer cells and that the latter two classes do not require functional p53 because they work equally well in cells with normal (wildtype), mutant or no p53. The two nickel complexes investigated in this dissertation, differ in their ability to cause DNA damage and cell death. The oxidized form of the nickel complex, [Ni(CR-2H)] 2+ causes DNA damage and cell death at a much lower concentration than its reduced counterpart [Ni(CR)] 2+ . The phenanthridine alkaloids, Sanguinarine and Chelerythine cause high levels of DNA strand breaks and extremely rapid apoptosis which is not due to DNA damage because the quick onset precludes extensive signaling. The effects of the phenanthridines were linked to production of large amounts of reactive oxygen species (ROS), in particular hydrogen peroxide (H 2 O 2 ). The importance of ROS for the action of anticancer drugs as well as antibiotics is increasingly being recognized. In addition we also investigated the thioxanthone Lucanthone or Miracil D (which was used for the treatment of parasitic worms more than 50 years ago). It causes DNA strand breaks and apoptosis. Apoptosis occurs on a timescale consistent with signaling. However, p53 does not seem to be involved and alternative mechanisms are being investigated. This work provides new directions for designing novel anticancer drugs that are not subject to the limitations of DNA damaging agents.
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Sostelly, Alexandre. "Mechanistic model-based drug development in the management of anticancer drugs resistance". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10203.
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La résistance aux chimiothérapies anticancéreuses constitue un problème majeur dans la prise en charge du cancer. Les transporteurs d'efflux contribuent à ce phénomène de résistance en altérant l'accumulation intracellulaire des cytotoxiques. Dans le passé, l'inhibition du transporteur d'efflux P-gp n'a pas permis de surmonter ce phénomène notamment à cause du manque de méthodes adéquates pour identifier et quantifier la pharmacologie des inhibiteurs d'efflux. Récemment de nouveaux inhibiteurs de BCRP, l'un des derniers transporteurs d'efflux découverts, ont été synthétisés permettant de retester l'intérêt de l'inhibition de ces transporteurs dans la prise en charge de la résistance aux anticancéreux. Néanmoins, afin d'éviter les mêmes écueils que lors du développement des inhibiteurs de P-gp, il est nécessaire d'utiliser d'autres approches telles que la modélisation mathématique dès le début du développement préclinique de ces inhibiteurs. Cette thèse a pour but de montrer les bénéfices de la modélisation et de la simulation dans le développement préclinique des inhibiteurs de transporteurs d'efflux et plus largement dans le développement des molécules anticancéreuses. L'exemple utilisé au travers de ce travail concerne l'étude de l'interaction entre l'irinotecan, un cytotoxique largement utilisé dans le traitement du cancer colorectal, et le MBLI87, un nouvel inhibiteur de BCRP. Deux principaux axes ont été abordés dans ce travail : - Le développement de modèles (semi-) mécanistiques à effets mixtes pour identifier et quantifier les facteurs impactant l'efficacité de la combinaison irinotecan-MBLI87 - Le développement de modèles d'inhibition de la croissance tumorale à effets mixtes pour évaluer précocement ce type d'interaction de traitements et pour optimiser la réponse tumorale. Les résultats obtenus avec l'approche de modélisation ont permis d'identifier certains des mécanismes tumoraux impactant l'efficacité des inhibiteurs de transporteur d'efflux. De plus cette approche s'est révélée supérieure aux approches classiques dans l'évaluation de ces molécules et dans l'optimisation de la réponse tumorale démontrant la puissance de la modélisation et de la simulation comme outil de développement des molécules anticancéreusesAnticancer drug resistance is a major issue in the management of cancer disease. Efflux transporters contribute to the multidrug resistance by altering the intracellular disposition of cytotoxic drugs. In the past, the inhibition of P-gp efflux transporter essentially failed because of the lack of adequate methods to identify their mechanisms of action. Recently, new inhibitors of BCRP, one of the latest efflux transporter that have been discovered, have been developed that allow re-testing the multidrug resistance inhibition through efflux inhibition. Nevertheless, to avoid the same issues of development as for P-gp inhibitors, new methods have to be used. This PhD work aims to demonstrate the benefits of mechanistic models to support the development of efflux transporter inhibitors and more generally of oncology compounds through two axes: - The development of mechanistic models of the interaction between cytotoxic and efflux transporter inhibitors - The development of quantitative tumour growth inhibition models to early evaluate oncology compounds and optimize patients’ response The results obtained with this approach allow the identification of key mechanisms of efflux transporter inhibitors and demonstrate the power of modelling and simulation to support oncology drug development
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PELLIZZONI, ELENA. "Molecularly imprinted polymeric nanoparticles for the therapeutic drug monitoring of anticancer drugs". Doctoral thesis, Università degli Studi di Trieste, 2016. http://hdl.handle.net/11368/2907991.
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La chemoterapia consiste nell’impiego di uno o di una combinazione di farmaci antitumorali per il trattamento del cancro. Tuttavia tali farmaci sono caratterizzati da una famacocinetica molto variabile e da una elevata tossicità che porta alla comparsa di molti effetti indesiderati nei pazienti, diminuendo l’efficienza della terapia. In questo contesto l’impiego del “Therapeutic Drug Monitoring” (TDM) risulta particolarmente importante in quanto permette per lo sviluppo di terapie personalizzate per i pazienti aumentando l’efficienza della terapia e la qualità della vita dei pazienti.
Questo progetto è finalizzato alla sintesi e allo sviluppo di sensori, basati su nanoparticelle polimeriche ad impronta molecolare, per i farmaci antitumorali: sunitinib, paclitaxel, SN38 e irinotecano, suo profarmaco.
Tali nanoparticelle solubili sono state ottenute mediante polimerizzazione radicalica ad elevata diluizione utilizzando diversi monomeri funzionali: N-acriloil-tirosina metil estere, N-acriloil triptofano metil estere, 4-vinilpiridina e 7-acrilossicumarina. La reazione è stata effettuata lasciando interagire i monomeri funzionali e il farmaco mediante interazioni deboli (legami idrogeno, π-staking, interazioni di Van der Waals) in DMSO e dopo l’aggiunta dell’acrilamide come co-monomero, dell’N,N’-etilenebisacrilamide come crosslinker e dell’iniziatore radicalico azobisisobitironitrile (AIBN) la polimerizzazione è stata ottenuta scaldando a 70°C per 4 giorni. La molecola templato è stata rimossa mediante dialisi prima in una miscela di metanolo e acido acetico, e poi in acqua. Le particelle ottenute dopo liofilizzazione, sono state caratterizzate mediante 1H-NMR, Nanosigh e Dynamic Laser Ligh Scattering. La capacità di legame e la selettività dei polimeri è stata studiata mediante test di recupero utilizzando un metodo HPLC per la quantificazione del farmaco catturato. Mentre le proprietà fluorescenti di alcuni dei polimeri sintetizzati sono state utilizzate per studiare le affinità di legame dei polimeri a basse concentrazioni di farmaco.
Il polimero contenente cumarina e specifico per il sunitinib è stato utilizzato come sensore fluorescente per lo sviluppo di un test di validazione in DMSO:plasma. Il sensore ha mostrato un’accuratezza del 15%, una precisione del 10% e una buona robustezza. Inoltre due diversi sensori fluorescenti sono stati sviluppati per la quantificazione dell’irinotecano in metanolo:plasma. Il primo sensore si basa sul quenching della fluorescenza intrinseca dell’irinotecano, mentre il secondo è un polimero molto fluorescente contenente un monomero funzionale con un gruppo naftalimidico la cui fluorescenza è spenta in seguito all’interazione con l’irinotecano.
Inoltre un test fluorimetrico e colorimetrico è stato sviluppato per quantificare il paclitaxel mediante la tecnica del “dye displacement”. Il test infatti, si basa sulla competizione tra il farmaco libero ed il farmaco legato covalentemente al DABCYL per il legame ad un polimero ad imprinting molecolare contenente EDANS come monomero funzionale fluorescente. Infatti il DABCYL è sia un colorante rosso, sia un FRET quencher dell’EDANS, perciò il suo legame nel polimero porta ad una variazione del colore e della fluorescenza del polimero.
Infine un test colorimetrico per la quantificazione dell’irinotecano è stato sviluppato utilizzando un polimero ad imprinting molecolare contenente l’acido 2-acrilamido-2-metil propansolfonico come monomero funzionale. Il test si basa sul legame del colorante: anilina gialla nei siti di legame del polimero rimasti liberi dopo interazione con i campioni di farmaco. L’interazione tra il colorante e l’acido solfonico nel polimero genera un cambio di colore da giallo a rosso.Chemotherapy consists in cancer treatment by the administration of a single or a combination of anticancer drugs. However chemotherapy agents are often characterized by an high variability of pharmacokinetic among patients and an high toxicity that leads to the appearance of many side effects decreasing the therapy efficiency. Therefore the therapeutic drug monitoring (TDM) become useful to develop personalized therapies for patients in order to increase the efficiency of the therapy and patient compliance. This project is aimed on the synthesis and development of specific sensors based on molecularly imprinted polymeric nanoparticles, to be applied in TDM of the anticancer drugs: sunitinib, paclitaxel, SN38 and its prodrug irinotecan. Soluble nanoparticles were obtained by high dilution radical polymerization with different functional monomers: N-acryloyl-tyrosine methyl ester, N-acryloyl-tryptophan methyl ester, 4-vinyl pyridine or 7-acryloyloxy-coumarin. The reactions were carried out allowing the functional monomer to interact with the drug by weak interactions (H-bonds, -staking and Van der Waals) in DMSO and after the addition of the co-monomer acrylamide, the crosslinker N,N’-ethylene bisacrylamide, and the radical initiator azobisisobutyronitrile (AIBN) the polymerization was achieved heating at 70°C for 4 days. The template was removed by dialysis first in methanol:acetic acid mixture and after in water. After the freeze-drying the polymers were characterized by 1H-NMR, Nanosight, and Dynamic Laser Light Scattering. The polymers binding capabilities and selectivity were investigated by rebinding tests using an HPLC method for the quantification of drug captured. while the fluorescence properties of some of these polymers were exploited to study the polymers binding affinities at low drug concentrations. The polymer containing coumarin and imprinted with sunitinib was used as fluorescence sensor to set up a validation test in DMSO:plasma mixture. The system showed an accuracy of 15%, a precision of 10% and a good robustness. Two different fluorescence sensors were also developed for irinotecan able to quantify the drug in methanol:plasma mixtures. The first sensor is based on the quenching of the intrinsic fluorescence of irinotecan, while the second is an highly fluorescence polymer containing a functional monomer with a naphthalimide mojety whose fluorescence is quenched upon interaction with the drug. Moreover the dye displacement technique was used to set up a fluorescent and colorimetric test for paclitaxel quantification. The test is based on the competition between the free paclitaxel and the drug covalently linked to DABCYL dye, for the binding in to an imprinted polymer containing EDANS fluorescent functional monomer. Since DABCYL is both a red dye and a FRET quencher of EDANS, its binding into the polymer gives a change in the polymer fluorescence and colour. Finally a colorimetric test for irinotecan quantification was developed using an imprinted polymer containing 2-acrylamido-2-methylpropane sulfonic acid as functional monomer. The test is based on the binding of aniline yellow dye in to the remaining free binding sites of the polymer after treatment with drug samples. The interaction between the dye and the sulfonic acid in to the polymer gives a change of colour from yellow to red.
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IACUZZI, VALENTINA. "Design of detection systems for the therapeutic drug monitoring of anticancer drugs". Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2967986.
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Considerato che la maggior parte dei farmaci antitumorali risulta caratterizzata da un'alta variabilità interindividuale nelle concentrazioni plasmatiche, che si riflette sull'efficacia del trattamento, durante il progetto di dottorato qui descritto sono state sviluppate tecniche per il loro monitoraggio terapeutico (TDM).
In primo luogo, è stato sviluppato, validato e cross-validato un metodo LC-MS/MS per la quantificazione di imatinib (IMA) e del suo metabolita attivo, norimatinib (norIMA), in pazienti affetti da tumore stromale gastrointestinale utilizzando la tecnica del dried blood spot (DBS). Il DBS consente di ridurre costi e tempi di campionamento e migliorare la compliance dei pazienti, poiché l’analisi viene effettuata tramite una goccia di sangue capillare depositata su carta. Da questa gli analiti vengono estratti con MeOH acidificato e l'estratto viene iniettato in un sistema LC (configurato con una cromatografia 2D per la pulizia on-line del campione), accoppiato ad un API-4000QT. Il metodo ha mostrato una buona linearità (R2> 0,996) nei range di 50-7500 ng/mL e 10-1500 ng/mL per IMA e norIMA. La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.1% e tra 88.9-112.8%, mentre quelle inter-day erano ≤6,6% e tra 95.7-104.3%, per entrambi gli analiti. Sono stati valutati inoltre: l'influenza dell'ematocrito (Hct), del volume depositato e dell'omogeneità del campione sull’analisi; la correlazione tra la concentrazione in DBS da prelievo venoso e da finger-prick (differenza tra -12 e 3.8%) e la stabilità dei DBSs (fino a 16 mesi). Il metodo è stato applicato per la quantificazione di 67 campioni DBSs di pazienti. Le concentrazioni in DBS, normalizzate per Hct e per un fattore di correzione che prescinde dall’Hct, correlano con quelle plasmatiche.
Parte del lavoro di questo progetto è stato anche dedicato allo sviluppo di strategie alternative a LC-MS/MS per favorire ulteriormente l’applicazione del TDM. In particolare, è stata eseguita la sintesi di polimeri (molecularly imprinted polymers - MIPs), con l'obiettivo futuro di applicarli come recettori in un sistema di rilevamento fluorimetrico per IMA. I MIPs sono stati sintetizzati sfruttando l'approccio non covalente e la polimerizzazione radicale ad alta diluizione. Tramite questa tecnica, i MIPs ottenuti, sintetizzati in DMSO e con acido metacrilico come monomero funzionale, presentano dimensioni nanometriche (dati acquisiti tramite dynamic light scattering). I tests di rebinding hanno dimostrato che solo 2 MIPs sono stati in grado di legare IMA con una buona specificità (rispetto ai corrispondenti polimeri non-imprinted) e selettività.
È stato infine sviluppato e validato un metodo LC-MS/MS per la quantificazione di ribociclib (RIBO), palbociclib (PALBO) e letrozolo (LETRO) in plasma. RIBO e PALBO sono farmaci appartenenti alla famiglia dei CDKIs recentemente approvati per il trattamento del carcinoma mammario in combinazione con LETRO. Il metodo messo a punto risulta adatto per l’applicazione nella pratica clinica, grazie ad una semplice preparazione del campione e ad una rapida analisi (6.5 min). Il metodo risulta lineare (R2 tra 0.992-0.983) nei range di concentrazione di 0.3-250 ng/mL per PALBO, 10-10000 ng/mL per RIBO e 0.5-500 ng/mL per LETRO (che coprono le concentrazioni plasmatiche terapeutiche). La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.6% e tra 94.5-112.3% per tutti e gli analiti, mentre quelle inter-day erano rispettivamente ≤7.3% e tra 94.5-112.9%. Il metodo è stato applicato con successo alla quantificazione di campioni plasmatici di pazienti.
In conclusione, con lo sviluppo di queste strategie si spera di implementare l’utilizzo del TDM per i farmaci oncologici nella pratica clinica.Despite the continuous progress in drug therapy, most anticancer drugs appear to be characterized by a high interindividual variability in plasma concentrations that is reflected in the efficacy of the treatment. From this arises the need of a personalized approach, so that the drug concentrations in plasma are adequate in each patient. On this basis, during the PhD project reported hereby, different techniques for therapeutic monitoring (TDM) of anticancer drugs were developed. First, a LC-MS/MS method for the quantification of imatinib (IMA) and its active metabolite, norimatinib (norIMA), was developed, validated and cross-validated in patients affected by gastrointestinal stromal tumour. This method allows to perform the quantification directly on a drop of capillary blood, exploiting the dried blood spot (DBS) technique, reducing sampling time, costs and improving patients’ compliance. Analytes were extracted from DBS samples by adding acidified methanol and the extract is injected into a LC system (configured with a 2D chromatography for online cleaning of the sample), coupled with an API-4000QT. The method showed good linearity (R2> 0.996) in the ranges of 50-7500 ng/mL and 10-1500 ng/mL for IMA and norIMA. Intra-day precision and accuracy were ≤3.1% and between 88.9-112.8%, respectively, while inter-day ones were ≤6.6% and between 95.7-104.3 %, for both analytes. Moreover, were also evaluated: the influence of the haematocrit (Hct), of the spot size and of the sample homogeneity on the analysis; the correlation between the concentration in DBS from venous sampling and from finger-prick (% difference between -12 and 3.8%) and the stability of DBSs (up to 16 months). Then, the method was applied for the quantification of 67 DBSs patients’ samples. Good agreement was obtained between IMA and norIMA concentrations found in DBS and plasma samples applying either the Hct normalization or avoiding it, simply multiplying the DBS concentration with a correction factor. Part of the work of this project was also dedicated for the development of alternative strategies for the quantification of anticancer drugs, to promote the application of TDM. In particular, the synthesis of molecularly imprinted polymers (MIPs) was performed, with the future goal of applying them as receptors in a fluorimetric detection system for IMA. MIPs were synthesized using the non-covalent approach and high dilution radical polymerization. Through this synthesis, the MIPs obtained, synthesized in DMSO with methacrylic acid as functional monomer, shown nanometric size (data acquired by dynamic light scattering). The rebinding tests then showed that 2 MIPs in particular were able to bind IMA with a good specificity (compared to the corresponding non-imprinted polymers) and selectivity. Finally, a LC-MS/MS method was developed and validated for the quantification of ribociclib (RIBO), palbociclib (PALBO) and letrozole (LETRO) in human plasma. RIBO and PALBO are drugs belonging to the CDKIs family, recently approved for breast cancer treatment in combination with LETRO. The method developed is suitable for its application in clinical practice, thanks to simple sample preparation and rapid analysis (6.5 min). The method showed a good linearity (R2 between 0.992-0.983) in the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng mL for RIBO and 0.5-500 ng/mL for LETRO (covering the therapeutic plasma concentrations). Intra-day precision and accuracy were ≤3.6% and between 94.5-112.3% for all and analytes, respectively, while inter-day ones were ≤ 7.3% and 94.5-112.9%. The method has been successfully applied for patients’ plasma samples quantification. In conclusion, with the development of these strategies there is the hope to implement the application of TDM for anticancer drugs in the clinical practice.
15
Marshall, Andrew James. "The development of PI3K inhibitors as anticancer drugs". Thesis, University of Auckland, 2010. http://hdl.handle.net/2292/6440.
Texto completo da fonteResumo:
Phosphatidylinositol 3-kinases (PI3Ks) are a lipid enzyme family that are vitally important
regulators of intracellular signalling pathways which control cellular activities including cell
survival, growth and proliferation. Deregulation of the PI3K signalling cascade has been
observed in a broad range of human diseases including cancer, diabetes, thrombosis, immunity
and inflammatory disorders. With the discovery of PI3K’s link to a variety of diseases, there has
been a race to produce ATP competitive inhibitors as therapeutic agents against the Class I PI3K
isozymes. Herein, compounds from two structurally distinct chemotypes were synthesised and
their activity and specificity characterized against isolated Class PI3K enzymes and two cellular
lines.
The aryl morpholine containing pyrido[1,2-a]pyrimidines probed the requirements of the Class
IA PI3K active sites through modification of the pendant C9 position. Interestingly, no
compound synthesised exhibited superior activity towards the p110β enzyme than TGX-221
(1.14). The second series of compounds probed the requirements of the thiazole-linked
pyrazolo[1,5-a]pyridine 4.41B, identified through scaffold hopping studies using the novel
p110α selective inhibitor PIK-75 (1.34). Although 4.41B was not synthetically accessible,
analogues explored alternative linkers and substitution of the 2-methyl-5-nitrobenzene ring, to
investigate the effect on p110α selectivity and potency. The sulfone-pyrazole linker group in
(5.5) was found to be critical, with alternative linker groups in the thiazole series SO2CH2 4.123,
CH2 4.122, CHOH 4.114 and linker absent 4.108 ablating activity, while activity was retained by
thiazole-CH2SO2 4.124.
As the complexes between the pyrido[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine chemotypes
with the active sites of p110β and p110α respectively are not known, docking simulations were
performed using structural p110β models and p110α (pdb:2RD0) respectively to understand the
molecular basis for the isoform selectivity exhibited by the two chemotypes. Suitable docking
methods were obtained by first investigating the ability of three docking protocols GOLD,
SURFLEX and AutoDock to find and correctly rank an experimentally derived conformation
both retrospectively (rescoring), where the compounds were docked back into the p110γ crystal,
and prospectively, where the ligands were docked into the apo p110α (2RD0).
16
Sobhanian, Ali. "Synthetic and spectral studies of potential anticancer drugs". Thesis, University of Hertfordshire, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361263.
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17
Mitchinson, Andrew. "New synthetic routes to polyamines and their use in receptor studies". Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481468.
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18
Lant, Neil Joseph. "The synthesis and evaluation of anti-melanoma drugs". Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341748.
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19
Bowman, Karen Julia. "Evaluation of novel compounds to modulate the cytotoxicity of anticancer agents in mammalian cells". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246707.
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20
Gonzaliez, Laura Maritza Calderon. "Design, synthesis and evaluation of a scaffold and capping units based on the pyrrolo[2,1-c][1,4]benzodiazepines for combinatorial chemistry". Thesis, University of Portsmouth, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302662.
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21
Wattanatorn, Wiboon. "Pharmacokinetics of 5-fluorouracil in cancer patients". Thesis, Robert Gordon University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389482.
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22
Priston, Melanie Jane. "Studies on the pharmacokinetics and metabolism of mitozantrone". Thesis, University of Exeter, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303766.
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23
Swingler, Lisa G. "An investigation of the induction of vincristine and multidrug resistance in Chinese hamster ovary cells following exposure to hydroxyurea or adriamycin". Thesis, University of York, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306289.
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24
Pireddu, Roberta. "New anticancer drugs : targeting tubulin and signal transduction pathways". Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/54618/.
Texto completo da fonteResumo:
The main aim of the study described in this thesis is the development of new anticancer agents. The first chapter is a general introduction to cancer, and the development of chemotherapy anticancer agents during the course of the years. The following four chapters briefly introduce the biological targets in the authors study. Chapter Two describes a general introduction to tubulin and microtubules as anticancer targets. A discussion of those compounds most relevant to this thesis is provided. Chapter Three describes Signal Transducers and Activator of Transcription 3 (STAT3) proteins, their role in cancer and the advances in the search of anticancer agent inhibitors of the STAT3 signalling pathway. Chapter Four focuses on the src homology 2 (SH2) domain containing tyrosine phosphatases SHP-2, a protein-tyrosine phosphatase implicated in pathogenesis of cancer and other human diseases. A brief discussion of the SHP-2 inhibitors is provided. Chapter Five describes the role of proteins Aurora kinases in cancer, promising targets for anticancer drug development, and the advances in the search of their inhibitors targeting the kinase activity at the ATP binding site. The following chapters (6-11) describe the authors own findings. Chapter six focuses on the design and synthesis and biological evaluation of novel styrylchromones, styrylquinazolones, and quinazolones as inhibitors of tubulin polymerization. Styrylchromones Styrylquinazolones Quinazolones Two series of isomeric styrylchromones were initially synthesized in order to establish the methoxy substitution pattern on the A ring favorable for optimal activity. The structure activity relationship on the B ring is also reported. Next, our strategy focused on identifying a chromone core replacement with improved potency. We directed our chemical efforts toward the synthesis of novel styrylquinazoline analogs. The quinazoline core would also provide easy access to the preparation of diverse sets of N-substituted derivatives (methyl and ethyl derivatives). Finally, a novel series of quinazolines were synthesized as conformationally-restricted analogs of chalcones. SAR was conducted around the quinazoline spacer between the aryl rings and systematically investigating the substituent effect in the B ring. Among the synthesized compounds we selected those analogues showing significant cytotoxicity (generally defined as IC50 value < 1.5 uM), and evaluated for activity in vitro tubulin polymerization inhibition assay. Chapter Seven focused on the identification of novel inhibitors of STAT3 dimerization. Computational analyses led us to the development of a T-shape model of molecules that can >2 occupy the pTyr-binding pocket of STAT3 SH2 domain. The rN"s' conjugate addition of nitromethane to a series of amides and the l/ J reduction of the nitro group were combined to give an easy route to onh j. the target T-shape molecules in a combinatorial fashion. The ksJJ methodology was also extended to amides activated by a nitro group. co2r observed a dramatic change in the course of the reaction, which Scaffold of T-shape molecules afforded a mixture of unexpected and unknown products, that each possessed an additional methylene group. A brief study into the mechanism was also conducted. Chapter Eight, Nine and Ten focuss on the development of Aurora kinases and SHP-2 inhibitors. Oxindole derivatives HL10581 and NSC117199 emerged as lead compounds from a high throughput screen for Aurora-A and SHP-2, respectively. f f Chapter Eight describes the synthesis of n-nfh Cl nnhN 2 several derivatives of HL10581 and H03SYYLo H03SYr>o NSC117199, directed to exploration of h h SAR around the oxindole moiety to HLiow.AAKfci-SMM nscii7,99,shp-2,,c5047 mM determine the structural features that are responsible for the activity. Chapters nine and ten report the biological evaluation of oxindole derivatives as inhibitors SHP-2 and Aurora kinases, respectively.
25
Harte, Robert J. A. "Pharmacokinetic evaluation of anticancer drugs using positron emitting nuclides". Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337702.
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Jung, Yongwon 1977. "Cellular responses against DNA damaged by platinum anticancer drugs". Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33746.
Texto completo da fonteResumo:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.Vita.
Includes bibliographical references.
The anticancer activity of platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin is mediated by their ability to attack DNA such that generated adducts trigger numerous cellular responses. A better understanding of these processes is critical for developing more effective therapeutic approaches, which can increase the anti-cancer activity of the drugs while minimizing side effects and extending successful treatment to a wider range of human cancers. Chapter 1 provides the current comprehension of early cellular responses to platinum-DNA adducts. The event primarily occurs through platinum-DNA adduct recognition by a number of cellular proteins. Among proteins that recognize platinum-DNA lesions, one class constitutes proteins that selectively recognize severely distorted DNA generated by the platinum adduct formation. The TATA-binding protein (TBP) and high mobility group protein HMGB1, both highly abundant and vital proteins, are reported to bind cisplatin- damaged DNA and to be involved in mediating the cytotoxic activity of platinum-based agents. Chapters 2 and 3 discuss the structural and kinetic properties of both proteins binding to platinated DNA.
(cont.) The TBP protein recognizes the TATA box element of transcriptional promoters and recruits other initiation factors. TBP binds with high affinity (Kd = 0.3 nM) to DNA containing site-specific cisplatin 1,2-intrastrand d(GpG) cross-links. The ko and koff values for the formation of these TBP complexes are 1-3 x 10⁵ M⁻¹s⁻¹ and [approx.] 1-5 x 10⁻⁴ sec⁻¹, respectively, similar to the corresponding values for the formation of a TBP-TATA box complex. When TBP was added to an in vitro nucleotide excision repair (NER) assay, it specifically shielded cisplatin-modified 1,2-(GpG) intrastrand cross-links from repair. HMGB1, a highly conserved non-histone DNA- binding protein, interacts with specific DNA structural motifs such as those encountered at cisplatin damage, four-way junctions, and supercoils. The full-length HMGB1 protein binds to DNA containing a 1,2-intrastrand d(GpG) cross-link mainly through domain A with a dissociation constant Kd of 120 nM. Interaction of the C- terminal tail with the rest of the HMGB1 protein was examined by EDC cross-linking experiments. The acidic tail mainly interacts with domain B and linker regions rather than domain A in HMGB1.
(cont.) Another group of proteins that encounter platinum-damaged DNA are involved with DNA function and therefore are in frequent contact with DNA. DNA, RNA polymerases and histone proteins inevitably run into platinum-DNA adducts. Transcription inhibition by DNA adducts of cisplatin is considered to be one of the major routes by which this anticancer drug kills cancer cells. Stalled RNA polymerases at platinum-DNA lesions evoke various cellular responses such as nucleotide excision repair, polymerase degradation, and apoptosis. The consequences of RNA polymerase blockage by platinum lesions are discussed in the next two chapters. T7 RNA polymerase and site-specifically platinated DNA templates immobilized on a solid support were used. Polymerase action is inhibited at multiple sites in the vicinity of the platinum lesion. The stalled polymerase can be dissociated from the DNA by subsequent polymerases initiated from the same template. The immediate consequences of human RNA polymerase (Pol) II arrest at the site of DNA damaged by cisplatin were studied in whole cells and cell extracts, with a particular focus on the stability of stalled Pol II and its subsequent ubiquitylation.
(cont.) Pol II was completely blocked by a cisplatin intrastrand cross-link and the stalled polymerase was quite stable in nuclear extracts as well as in cisplatin-treated HeLa cells. The stalled Pol II proteins were transcriptionally active and capable of resuming transcription beyond the DNA adduct following its chemical removal from the template. A series of experiments revealed that lysines other than Lys-48 of ubiquitin are involved in Pol II ubiquitylation following DNA damage. Only a fraction of ubiquitylated Pol II dissociates from damage sites and that it is rapidly destroyed by proteosomes. In the final chapter, hapten-conjugated platinum compounds were studied in an effort to follow DNA damaged by platinum agents in living cells. Platinum complexes containing a desthiobiotin moiety (DTB-Pt) with different linkers were synthesized and characterized in vitro and in cells. DNA damaged by DTB-Pt was strongly interacted with streptavidin-coated beads. Moreover, less than 1 fmol of DTB-Pt DNA adduct can be detected by using a simple dot blot analysis.
by Yongwon Jung.
Ph.D.
27
Elsaid, Z. "Nanocarriers for the delivery of anticancer drugs and siRNA". Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1467125/.
Texto completo da fonteResumo:
Background and Purpose: Optimal benefit in the treatment of lung cancer is impeded due to systemic side effects, sub-therapeutic drug levels at the tumour site and the development of multidrug resistance. This thesis describes three related but distinct strategies aimed at enhancing drug treatment of lung cancer. Methods: The first approach entails design of micelles using three amphiphilic derivatives of chitosan (TPGS-chitosan, retinoic acid-chitosan-PEG and lipoic acid-chitosan-PEG (LACPEG)) for the pulmonary delivery of siRNA. Polymers where characterized using FT-IR and 1H NMR. Micelles prepared from these polymers were characterised for their size, zeta potential, morphology and toxicity in A549 and PC-9 cells. Micelle complexation with siRNA was assessed using agarose gel electrophoresis and the PicoGreen assay. Gene knockdown was assessed by MTS assay and western blotting. LACPEG and LACPEG/DSPE-PEG nanocarriers were loaded with gefitinib and re-characterised for their physicochemical properties, entrapment efficiency and activity (cell death) in vitro. In vivo biodistribution of these nanocarriers was assessed in CT26 and LLC-tumour bearing BALB/c and C57BL6 mice, respectively. The third approach to drug delivery employed mixed nanocarriers of DSPE-PEG or TPGS and PLGA-PEG, for co-delivery of gefitinib and genistein. Results: Successful synthesis of amphiphilic derivatives of chitosan. Further optimisation needed for micelles prepared using the first strategy with respect to siRNA complexation, as although 100% complexation was observed using agarose gel electrophoresis and the PicoGreen assay, at an NP ratio of 1:160, this was not reflected in cell culture. LACPEG micelles, showing the smallest size, best stability and lowest toxicity, were further studied and mixed with micelles of DSPE-PEG, for improved loading of gefitinib (45% compared to 80%). These showed improved antitumour activity in vitro and whole body prolonged circulation with tumour accumulation and uptake in vivo. Similar results were obtained with gefitinib and genistein mono- and co-loaded PLGA-PEG/TPGS nanocarriers. Conclusion: LACPEG/DSPE-PEG and PLGA-PEG/TPGS nanocarriers showed promise for the delivery of anticancer drugs, demonstrating a synergistic activity from the carrier itself, as well as the co-delivery of both therapeutic molecules. Further studies are warranted for siRNA complexation.
28
Bezoski, Brittany A. "Metal Binding Characteristics of Heterocyclic and Carbocyclic Anticancer Drugs". University of Toledo Health Science Campus / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1481287656969232.
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TOMMASINI, MARTINA. "Fluorescent Molecularly Imprinted Polymers as sensors for anticancer drugs". Doctoral thesis, Università degli Studi di Trieste, 2019. http://hdl.handle.net/11368/2952847.
Texto completo da fonteResumo:
Chemotherapy is a medical treatment mainly aimed at damaging solid and haematological tumors, by the administration of specific drugs able to target cancer cells. These drugs, however, often show many secondary effects and present variable inter-individual pharmacokinetics. Hence, the ideal optimization of the therapy would consist of continuously monitoring, in each patient, drug absorption in blood circulation, in order to adjust the daily dose regimen, decreasing therefore its side effects and improving the whole treatment. This methodology is known as Therapeutic Drug Monitoring (TDM) and requires the determination of drug concentration in various biological matrix, as blood, plasma, urine or saliva, and evaluation of these concentrations in terms of relevant clinical parameters. The main goal of TDM consists of individualization of therapeutic treatment of the patient.
However, TDM application usually involves the support of specific instrumentations, as HPLC-MS or LC-MS/MS, that allow to perform an accurate and precise analysis of the samples, but they result time consuming, expensive and require trained personnel. Thanks to the recent technological developments, it is possible to miniaturize all of this, towards the design of specific Point-of-Care (POC) devices, able to perform a rapid quantification of the sample, without requirement of clinical support. The main advantages of using POC devices are portability, inexpensiveness and easiness to handle, hence to be used directly from patients themselves.
This work is part of the project “Application of Advanced Nanotechnology in the development of innovative cancer diagnostic tools”, funded by Associazione Italiana Ricerca Cancro (AIRC) and coordinated by Centro di Riferimento Oncologico di Aviano (CRO); one of its aims consists of the development of Point-of-Care devices to be used for the Therapeutic Drug Monitoring of several anticancer drugs, included irinotecan and imatinib. This thesis project is focused, in particular, on the development of artificial receptors, named Molecularly Imprinted Polymers (MIPs), that can act as sensors for antitumor agents irinotecan and imatinib detection in human plasma samples. MIPs have been prepared by incorporating various fluorescent functional monomers in the polymer matrix, in order to obtain a fluorescent sensor, acting as recognition element and transducer at the same time. Different fluorescent 1,8-naphtalimide and a polymerisable EDANS derivatives have been synthesized; the interactions of these monomers and of fluorescein O-acrylate (commercially available) with each anticancer drug were investigated through NMR experiments. After selection of the best monomer-drug match, several MIPs have been prepared for each target molecule, following a high dilution radical polymerization protocol, and characterized by Dynamic Laser Light Scattering (DLS) and Transmission Electron Microscopy (TEM); nanoparticles with an average diameter of 15 nm were obtained. The MIPs rebinding capacity and specificity were studied through HPLC assays in water, and, exploiting their intrinsic fluorescence properties, it was possible to investigate on their rebinding capabilities in different media, by observing the eventual quenching of fluorescence upon binding.
A MIP designed for irinotecan, in particular, containing a naphtalimide fluorescent dye, showed very promising results, as best specificity in water and an optimal drug sensitivity within its therapeutic concentrations range (17 nM – 17 μM), also in samples of plasma treated with acetonitrile (LOD 9.4 nM with within-run variability 10% and day to day variability 13%).
The bes MIP for imatinib, instead, was obtained by incorporation of EDANS fluorophore in the polymerix matrix; at fluorescence measurements, MIP showed both a good specificity and rebinding capacity toward the imatinib in water (LOD of 1.7 μM and within-run variability 4.4%).
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Pekcagliyan, Gonul. "Synthesis Of Topoisomerase Inhibitor Type Anticancer Drugs Linked Gold Nanoparticles". Master's thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/3/12609270/index.pdf.
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This study presents studies on camptothecin (CPT), a potent antitumor agent in order to improve its stability and solubility without reducing its activity. The work describes the modification of camptothecin at 20-OH position a new strategy to overcome the stability and solubility problems of the free drug. Camptothecin is conneted to linker that could be processed to a terminal thiol group and this thiol group was connected to gold surface, to obtain CPT-gold nanoparticles.
In the first part of the studyundecenol was chosen as the starting material and reacted with azobisisobutylonitrile to obtain S-11-hydroxyundecyl ethanethioate. 11-hydroxyundecyl ethanethioate was reacted with NaOMe to synthesize the target linker 11, 11&rsquo
-disulfanediyldiundecan. After synthesis of the target linker, the 20- OH functional group of CPT was replaced with this linker to obtain 20- (11, 11&rsquo
-disulfanediyldiundecan) - captothecin. The second part of the study, gold nanoparticles were synthesized by using HAuCl4 solution and the camptothecin derivative containing thiol group at 20-OH position was connected to the gold surface.
31
Karlsson, Henning. "New preclinical strategies for characterization and development of anticancer drugs". Doctoral thesis, Uppsala universitet, Cancerfarmakologi och beräkningsmedicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330999.
Texto completo da fonteResumo:
Increased understanding of the molecular mechanisms underlying cancer development has shifted drug discovery towards target driven drug development the last decades, but the development of effective cancer drugs has been hampered by the lack of predictive preclinical models. 3-D cultures, considered to more accurately reflect solid tumors in vivo, have been proposed as one way to increase the predictability of clinical efficacy in cancer drug discovery and development. The aims of this thesis were to improve preclinical models for cancer drug development, with focus on colorectal cancer (CRC) and use of multicellular tumor spheroids (MCTS), and also to mechanistically characterize some potentially new anticancer drugs (papers I – IV). The most important technical improvement was the development of direct measurement of green fluorescent protein (GFP) marked cells in spheroids, simplifying live collection of viability data and enabling high-throughput screening (HTS) in the MCTS model (paper I). In paper III and IV, the 3-D model was adapted to enable studies on the interaction between drugs and radiation. Two potentially new anticancer drugs, VLX50 and VLX60, were mechanistically characterized. VLX60, a novel copper containing thiosemicarbazone, induced reactive oxygen species (ROS) formation, was selectively active against BRAF mutated colon cancer cells and exhibited anticancer activity in vivo (paper II). Furthermore, two potentially new anticancer drugs were found suitable for further development for use in combination with radiation (papers III and IV). In paper III, synergy with radiation in spheroids compared to monolayer cultured colon cancer cells was shown with the novel iron-chelating inhibitor of oxidative phosphorylation, VLX600. In paper IV, the antiprotozoal drug nitazoxanide was shown to sensitize quiescent clonogenic colon cancer cells to radiation. In conclusion, introduction of measurement of fluorescence of GFP marked cells in spheroids makes clinically relevant 3-D models feasible for HTS experiments and characterization of candidate drugs and radiosensitizers in early cancer drug discovery and development. VLX60 has several characteristics suitable for further development into a cancer drug, notably against BRAF mutated colorectal cancer cells. VLX600 and nitazoxanide show radiosensitizing properties making them promising for further development for use as cancer drugs in combination with radiation.
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Liu, Bo. "Template-assembled synthetic G-quartets as targets for anticancer drugs". Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42814.
Texto completo da fonteResumo:
DNA is a classic target for small-molecule ligands. In order to reduce significant toxicities of anticancer drugs resulting from unspecific interactions with DNA duplexes, it aroused great interest to investigate the specific interactions of ligands with a secondary DNA structure, G-quadruplex, formed by a guanine-rich DNA sequence. Induction and stabilization of G-quadruplex structures by ligands have been shown to inhibit telomerase activities and regulate the transcription and expression levels of oncogenes in cancer cells; therefore, the design of synthetic G-quartets under physiological conditions as minimal models of G-quadruplexes or artificial receptors of anticancer drugs has become an important and promising approach to clarify binding mechanisms, as well as to develop practical high-performance anticancer drugs. This thesis explores the recognition behavior of the second generation of hydrophilic template-assembled synthetic G-quartets (TASQs) using fluorescence spectroscopy and CD spectroscopy with PIPER, TMPyP4, AZATRUX, BSU 1051 and BRACO-19. The results show that PIPER, TMPyP4, AZATRUX can stack on top of a G-tetrad plane via π-π stacking with stoichiometries of 1:1 and high binding affinities (KPIPER=1.65×10⁷ M⁻¹, KTMPyP4= 8.5×10⁵ M⁻¹, KAZATRUX=2.55×10⁶ M⁻¹); however, BSU 1051 and BRACO-19 have no such behavior with TASQs. All the spectra and binding mechanisms are similar to known mechanisms or computer-aided molecular simulation models, suggesting that the second generation of hydrophilic TASQs can imitate the natural terminal G-tetrad planes of G-quadruplexes. Moreover, this artificial receptor has selectivity over different ligands with an ability to contribute to the screening of small-molecule ligands, as well as the investigations of binding mechanisms of new anticancer ligands.
The main works in this thesis are shown as follows:
1. Introduction to DNA duplexes, G-quadruplexes, template-assembled synthetic G-quartets, anticancer drugs (i.e. PIPER, TMPyP4, AZATRUX, BSU-1051, BRACO 19, telomestatin), and characteristic methods.
2. Synthesis of water-soluble template-assembled G-quartets (TASQ 13), PIPER, and AZATRUX. The binding properties of these ligands with TASQ 13 were characterized by spectroscopic methods so as to show the binding abilities and binding modes of different drugs to TASQ 13.
3. Conclusions and future work.
33
Cadete, pires Ana cristina. "Hyaluronic acid nanocapsules for the intracellular delivery of anticancer drugs". Thesis, Angers, 2016. http://www.theses.fr/2016ANGE0071.
Texto completo da fonteResumo:
Cette thèse de doctorat avait pour principal objectif le développement d’une méthode viable pour la formulation de nanocapsules d’acide hyaluronique (NCs HA) à des fins d’incorporation et de libération intracellulaire d’agents anticancéreux. La première étape de ce travail a visé le développement d’une méthode d’émulsion spontanée dans laquelle les NCs HA ont été formulées sans avoir recours à des solvants organiques, ni à un travail à haute température ou à un apport énergétique élevé, ce qui fournit des conditions optimales pour l’incorporation de biomolécules sensibles tout en diminuant l’impact environnemental. Un autre avantage de ce système est basé sur l’utilisation d’un dérivé de l’acide hyaluronique modifié hydrophobiquement, ce qui permet la formulation de NCs HA par des interactions hydrophobes, réduisant ainsi la toxicité due à l’addition d’un surfactant cationique. Une fois formulées, les NCs HA étaient caractérisées par une taille de 130 nm et un potentiel zeta négatif de -20 mV. La versatilité de ce nanotransporteur a été confirmée par l’incorporation de différentes molécules : le docétaxel, un agent cytostatique, a été incorporé au sein du coeur huileux, tandis que l’anti-gasdermin B, un anticorps monoclonal, a été piégé au sein de l’enveloppe polymérique. Le taux d’encapsulation du docétaxel était élevé, sa libération contrôlée et sa cytotoxicité maintenue sur la lignée cellulaire A549 de cancer du poumon. Enfin, l’anti-gasdermin B a été associée avec succès à l’enveloppe polymérique de NCs HA et, une fois à l’intérieur de la cellule, l’anti-gasdermin B était capable d’échapper au compartiment endosomal et d’effectivement cibler la protéine intracellulaire gasdermin B, entraînant une importante diminution du comportement migratoire et invasif des cellules de la lignée HCC1954 de cancer du sein. Tous ces résultats mettent en évidence le potentiel de NCs HA auto-émulsifiées en tant que systèmes multifonctionnels pour transporter divers agents anticancéreux, en particulier pour la libération intracellulaire d’anticorps monoclonaux, une approche ambitieuse qui pourrait passer au premier plan parmi les stratégies innovantes dans la lutte contre le cancerThe main goal of this thesis has been the development of hyaluronic acid nanocapsules (HA NCs) as a multifunctional platform for the encapsulation and delivery of diverse anticancer drugs, such as hydrophobic drugs and hydrophilic biomolecules. The first step was the development of a spontaneous emulsification method, where HA NCs were formulated without the need of organic solvents, heat or high energy input, providing conditions for the incorporation of sensitive biomolecules while decreasing the environmental impact. Another advantage of this system is based on the use of a hydrophobically-modified HA derivative that allowed the preparation of HA NCs by hydrophobic interactions rather than electrostatic forces and thus, reducing the toxicity associated to the addition of a cationic surfactant as a counterion. Once formulated, HANCs had a size around 130 nm and a negative zeta potential about -20 mV. Moreover, these nanocapsules were markedly stable under storage conditions and diluted in human plasma, taking forward this system as a potential carrier for intravenous administration. The versatility of this nanocarrier was confirmed by the incorporation of different molecules : docetaxel, a cytostatic drug, was incorporated into the oil core, whereas anti-gasdermin B, a monoclonal antibody, was entrapped into the polymeric shell. Docetaxel was highly encapsulated, released in a sustained manner and its cytotoxicity in A549 lung cancer cell line was maintained. Finally, anti-gasdermin B was successfully associated to the polymeric shell of HA NCs and its intracellular delivery confirmed by confocal microscopy. Once inside the cell, anti-gasdermin B was able to escape the endosomal compartment and to target the intracellular protein gasdermin B, promoting an important decrease in the migratory and invasive behavior of HCC1954 breast cancer cell line. All these results highlight the potential of self-emulsifying HA NCs as multifunctional systems to transport diverse anticancer drugs, with special emphasisin the intracellular delivery of monoclonal antibodies, an ambitious challenge that could open new avenues to fight cancer
En esta tesis se describe el desarrollo de un nuevo método sostenible para la elaboración de nanocápsulas de ácido hialurónico (NCs HA) como una nueva estrategia para el tratamiento del cáncer. Estas nanocápsulas permiten la incorporación de diferentes moléculas terapéuticas, tanto hidrofóbicas como hidrofílicas, y promueven su liberación en el interior de las células tumorales. En primer lugar, se desarrolló un método de autoemulsificación para la preparación de las NCs HA sin el uso de disolventes orgánicos, temperatura o aplicación de energía. Estas condiciones son ideales para la incorporación de biomoléculas lábiles, así como para reducir el impacto medioambiental del proceso. Otra ventaja del sistema reside en el uso de un derivado de HA modificado hidrofóbicamente que permite la formulación de las nanocápsulas sin la adición de un tensoactivo catiónico, reduciendo así la posible toxicidad del sistema. Las NCs HA semantuvieran estables en condiciones de almacenamiento y tras su dilución en plasma, manteniendo un tamaño nanométrico (130 nm) y una carga superficial negativa (-20mV), lo que corrobora su potencial para administración intravenosa. La versatilidad de este nanosistema fue confirmada mediante la incorporación de diferentes moléculas : docetaxel, un fármaco citostático encapsulado en el núcleo oleoso, y anti-gasdermina B, un anticuerpo monoclonal asociado a la cubierta polimérica. El docetaxel fue eficazmente encapsulado, manteniendo su citotoxicidad en la línea celular de cáncer de pulmón A549, mostrando una liberación del sistema de un modo controlado. Finalmente, la anti-gasdermina B fue asociada de manera eficaz a la cubierta poliméricade las NCs HA y su liberación intracelular confirmada por microscopía confocal. Una vezen el interior de la célula, la anti-gasdermina B abandonó el compartimento endosomaly bloqueó de manera efectiva la proteína intracelular gasdermina B, promoviendo así una importante reducción de la migración e invasión de las células HCC1954 de cáncer de mama. Estos resultados ponen de manifiesto el potencial de las NCs HA, preparadas por auto-emulsificación, como sistemas multifuncionales para transportar diversos fármacos, con especial énfasis en la liberación intracelular de anticuerpos monoclonales,una estrategia ambiciosa en la lucha contra el cáncer
34
Figueiredo, João Daniel Amaral. "The effect of anticancer drugs prodiginines in PP1 in melanoma". Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/6861.
Texto completo da fonteResumo:
Mestrado em Biomedicina MolecularUm dos principais mecanismos reguladores da função celular é a fosforilação de proteínas. É de focar que a fosforilação anormal de proteínas-chave pode estar associada a várias patologias, incluindo o cancro. Embora já existam muitos estudos sobre cinases no cancro, o conhecimento sobre as fosfatases que antagonizam a acção das cinases é muito menos. A PP1, uma das principais proteínas fosfatase de serina/treonina expressa em todas as células eucarióticas, está envolvida em vários processos celulares incluindo apoptosis e ciclo celular. Na realidade, diversos estudos demonstram que a PP1 regula variadas proteínas que são elementos-chave no processo de tumorigenesis. A AKT, uma cinase serina/treonina que se encontra desregulada em vários tipos de cancro, é um factor crucial na progressão e sobrevivência de melanoma. Prodigiosina, um membro da família de metabolitos secundários tripirrolicos pigmentados de vermelho, as prodigininas, demonstra propriedades anticancerigenas em vários tipos de cancro. Na verdade alguns estudos verificaram que a AKT é desfosforilada pela prodigiosina embora ainda seja desconhecido o mecanismo pelo qual tal acontece. Dada a importância da AKT na progressão e sobrevivência do melanoma e a capacidade da PP1 em desfosforilar a AKT é possível que a PP1 esteja envolvida em tal mecanismo. Os resultados preliminares demonstraram que a PP1 liga-se a um membro da família das prodigininas provando a interacção entre estas moléculas. Por outro lado, ensaios em linhas celulares de melanoma usando tratamentos com prodigiosina e cantaridina, um inibidor da PP1, demonstraram que a prodigiosina afecta isoformas da PP1 diferencialmente. Estes resultados sugerem que a prodigiosina actua em duas vias de sinalização distintas em melanoma, a via da AKT e a da MAPK, uma vez que alteração nos níveis de PP1α, uma das isoformas da PP1, se correlaciona com a variação dos níveis de fosforilação da AKT e as mudanças nos níveis da PP1γ com a variação dos níveis de fosforilação da MAPK. Com estes resultados propomos um modelo de como a prodigiosina desfosforila a AKT e como este processo contribui para a indução da morte celular em células de melanoma. Esperamos que este modelo ajude na compreensão do mecanismo de acção da prodigiosina bem como no reconhecimento das fosfatases como novos alvos terapêuticos no tratamento de cancro.
Protein phosphorylation is a major regulatory mechanism for cell function. It is noteworthy that several pathologies, including cancer to be associated with abnormal phosphorylation of key proteins. Although many studies have addressed the kinases that are misregulated in cancer, much less is known about the phosphatases that counteract their actions. PP1, a major serine/threonine protein phosphatase that is ubiquitously expressed in all eukaryotic cells, is involved in many cellular processes including apoptosis and cell cycle. In fact, several studies demonstrate that PP1 regulates several proteins that are key elements in the tumorogenesis process. AKT, a serine/threonine kinase that is disregulated in several types of cancer is a crucial factor in melanoma progression and survival. Prodigiosin, a family member of the natural red pigmented tripyrrolic secondary metabolites, prodiginines, show anticancer properties in numerous types of cancer. In fact, some prodigiosin studies demonstrate that AKT is dephosphorylated by prodigiosin by an unknown mechanism. Given the importance of AKT in melanoma progression and survival and the capacity of PP1 to dephosphorylate AKT it is possible that PP1 is involved in this mechanism. Our preliminary results showed that PP1 binds to one member of prodiginine family proving the interaction between these molecules. On the other hand, experiments with melanoma cell lines, using prodigiosin and cantharidin, a PP1 inhibitor, treatments, demonstrate that prodigiosin affect differently PP1 isoforms. These results suggest that prodigiosin acts in a different way in two altered pathways in melanoma, AKT and MAPK, since the alterations in PP1α levels, one of PP1 isoforms, are correlated with the conversion in AKT dephosphorylation and the variations in PP1γ levels with the changes in MAPK dephosphorylation. Given these results we propose a model of how prodigiosin dephosphorylates AKT and how this process contributes to induce cell death in melanoma cells. We expect that this model helps to understand prodigiosin action mechanism as well as acknowledge phosphatases as a therapy target in cancer treatment.
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Carmichael, Samantha Jane. "Optimisation of study design in the pharmacokinetics of anticancer drugs". Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23290.
Texto completo da fonteResumo:
"Optimal sampling strategies" are based upon the concept of 'information-rich' times within a concentration-time profile. In this thesis, the selection of optimal sampling times was based on sensitivity analysis and applied to the one and two-compartment PK models. Simulation studies were used to show that parameter estimates obtained using an optimal design method with a reduced number of samples were as good as, if not better than, those obtained from PK studies in which the sampling times were selected empirically. In addition, the effect of adding sampling windows around the "optimal" times offered improved estimation of the inter-subject variability parameters, when compared to designs with fixed sampling times. This result has particular relevance in a clinical setting where a sample may not be collected at the stipulated time, but is still useful in the analysis if the "actual" sampling time is recorded accurately. Further simulations were based on published sampling designs for the anticancer drug carboplatin, and these were used for comparison with the results when an "optimal design" was used. Finally, a population analysis was carried out on data from a phase I clinical trial of the broad-spectrum neuropeptide antagonist, Antagonist G. The parameter values were used to design on "optimal" sampling strategy. As the sample times of the optimal strategy were different to those used in the clinical study, further simulations were used to compare the design. Using sensitivity analysis to design sampling strategies for population PK studies allowed the selection of a minimum number of sampling times, but still resulted in accurate estimation of the parameters of the one and two-compartment PK models. These sampling times provide a basis for PK study design, around which further samples could be added to improve the identification of the model and also the estimation of parameters and their inter and intra-subject of variability.
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CONSONNI, ELISA. "Anticancer drugs mechanism of action investigated by advanced biomolecular tools". Doctoral thesis, Università degli Studi di Milano, 2005. http://hdl.handle.net/2434/61944.
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Pixantrone (BBR2778), a DNA intercalating agent topoisomerase II inhibitor, belongs to the aza-anthracenedione chemical class and is currently under clinical investigation in non-dgkn iymphomas (NHLs)
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Ferrari, E. "PHARMACOGENOMIC APPROACHES TO IDENTIFY AND CHARACTERIZE TARGETS OF ANTICANCER DRUGS". Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/155506.
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Encouraging clinical studies are recently showing how a number of anticancer compounds work through a synthetic lethal mechanism by targeting pathways that are specifically essential for the viability of cancer cells but not of normal cells.
We applied the concept of synthetic lethality by performing yeast high-throughput screens to define the chemical-genetic profile of three chemotherapeutic drugs: cisplatin, ecteinascidin, 5-fluorouracil.
By means of the DDR-library, a collection of mutants defective in the DNA damage response, we identified the DNA repair pathways required to survive to the under investigation compounds: DSBR through HR, NER and PRR for cisplatin, DSBR, NER for ET-743, DSBR through HR for 5-FU. Importantly, we also defined the pathways whose absence leads to resistance: MMR and NHEJ for cisplatin, NER, MMR and NHEJ for 5-FU.
By exploiting the complete knockout collection YKO-library, we analyzed in detail the yeast proteins involved in cisplatin and ET-743 response. Ecteinascidin-screen revealed that the lack of factors belonging to Swi/Snf complex, Swr1 complex and Mms4-Mus81 endonuclease causes hypersensitivity, while the absence of Slx5-Slx8 dymer leads to resistance. Through the cisplatin-screen, besides confirming the results obtained through the DDR-library, we determined the involvement of these proteins in CDDP survival: Rts1, B-type regulatory subunit of protein phosphatase 2A, Wss1, SUMO-dependent isopeptidase and Irc21, whose function had never been defined.
Given the lack of knowledge on Irc21, we undertook a series of different approaches to identify Irc21 cellular role, finding interesting connections with mitochondria-, recombination- and chromatin remodeling-functions.
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Shahbakhti, Hassan. "Structure/activity relationships of antitumour diazridinylquinones". Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308289.
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Mi, Zihou. "Chemical Dynamics of Camptothecin Anticancer Drugs in Human Blood: Impact on Drug Stability and Activity /". The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487930304688618.
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Wang, Han. "Developing Novel Drug Delivery Systems For Platinum-based Anticancer Drugs Using Coordination-driven Self-assembly". Kent State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=kent1595260147978142.
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LA, FRANCA Mery. "Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors". Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/475964.
Texto completo da fonteResumo:
Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues.
Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types.
It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules.
In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+.
The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia.
After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.
42
Celik, Haydar. "Enzyme-catalyzed Reductive Activation Of Anticancer Drugs Idarubicin And Mitomycin C". Phd thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/3/12609247/index.pdf.
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Idarubicin (IDA) and mitomycin C (MC) are clinically effective quinone-containing anticancer agents used in the treatment of several human cancers. Quinone-containing anticancer drugs have the potential to undergo bioreduction by oxidoreductases to reactive species, and thereby exert their cytotoxic effects. In the present study, we investigated, for the first time, the potential of IDA, in comparison to MC, to undergo reductive activation by NADPH-cytochrome P450 reductase (P450R), NADH-cytochrome b5 reductase (b5R) and P450R-cytochrome P4502B4 (CYP2B4) system by performing both in vitro plasmid DNA damage experiments and enzyme assays. In addition, we examined the potential protective effects of some antioxidants against DNA-damaging effects of IDA and MC resulting from their reductive activation. To achieve these goals, we obtained P450R from sheep lung, beef liver and PB-treated rabbit liver microsomes, b5R from beef liver microsomes and CYP2B4 from PB-treated rabbit liver microsomes in highly purified forms.
The plasmid DNA damage experiments demonstrated that P450R is capable of effectively reducing IDA to DNA-damaging species. The effective protections provided by antioxidant enzymes, SOD and catalase, as well as scavengers of hydroxyl radical, DMSO and thiourea, revealed that the mechanism of DNA damage by IDA involves the generation of ROS by redox cycling of IDA with P450R under aerobic conditions. The extent of DNA damages by both IDA and MC were found to increase with increasing concentrations of the drug or the enzyme as well as with increasing incubation time. IDA was found to have a greater ability to induce DNA damage at high drug concentrations than MC. The plasmid DNA experiments using b5R, on the other hand, showed that, unlike P450R, b5R was not able to reduce IDA to DNA-damaging reactive species. It was also found that in the presence of b5R and cofactor NADH, MC barely induced DNA strand breaks. All the purified P450Rs reduced IDA at about two-fold higher rate than that of MC as shown by the measurement of drug-induced cofactor consumption. This indicates that IDA may be a more potent cytotoxic drug than MC in terms of the generation of reactive metabolites. The results obtained from enzyme assays confirmed the finding obtained from plasmid DNA experiments that while MC is a very poor substrate for b5R, IDA is not a suitable substrate for this enzyme unlike P450R. The reconstitution experiments carried out under both aerobic and anaerobic conditions using various amounts of CYP2B4, P450R and lipid DLPC revealed that reconstituted CYP2B4 produced about 1.5-fold and 1.4-fold rate enhancements in IDA and MC reduction catalyzed by P450R alone, respectively. The present results also showed that among the tested dietary antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, only quercetin was found to be highly potent in preventing DNA damage by IDA.
These results may have some practical implications concerning the potential use of P450R as therapeutic agent on their own in cancer treatment strategies. Selective targeting of tumor cells with purified P450R by newly developed delivery systems such as using polymers, liposomes or antibodies may produce greater reductive activation of bioreductive drugs in tumor cells. Consequently, this strategy has a high potential to increase the efficacy and selectivity of cancer chemotherapy.
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Mellish, Kirstie Joanne. "The cellular and molecular pharmacology of novel platinum-based anticancer drugs". Thesis, Institute of Cancer Research (University Of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242998.
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Ward, T. H. "Bioreductive anticancer drugs : a comet study on mechanisms and DNA damage". Thesis, University of Salford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245022.
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Walton, Michael Ian. "The effects of hyperthermia on the pharmacokinetics of selected anticancer drugs". Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254220.
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46
Alzahrani, Mona Moshref. "Development of New Vanadium and Iron complexes for potential anticancer drugs". DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2016. http://digitalcommons.auctr.edu/dissertations/2877.
Texto completo da fonteResumo:
In recent years, metals based antitumor complexes have played an important role in chemotherapy. In this study, two new metal complexes - dioxovandium LVO2 and dichloroiron LFeCl2-have been synthesized. The dioxovanadium complex LVO2 is formed from the reaction between the ligand HL and VO(acac)2 in 1:1 molar ratio, while the dichloroiron complex was prepared from the reaction between ligand HL with FeCl2 in 1:2 molar ratio. Both new complexes have been characterized by FT -IR and UV -Vis.
The IR spectrum revealed the absorption band changes between the complexes and their ligand, and UV -Vis show d-d transitions for the iron complex and LMCT for the vanadium complex. Molecular structures of the two complexes have been determined by X-ray crystallography. The central metals (both vanadium and iron) have adopted distorted trigonal bipyramidal configurations. The ligand serves as tridentate providing two nitrogen and one oxygen atoms for coordination. The complexes with vanadium and iron central atoms have shown promising results in preclinical testing and have already been evaluated for enhancement of the anti-proliferative activity on PC3. All three compounds HL, LVO2, and LFeCh displayed high cytotoxicity toward prostate cancer cell line.
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Yang, Jianning. "Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434.
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LA, FRANCA Mery. "Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors". Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/491643.
Texto completo da fonteResumo:
Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues.
Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types.
It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules.
In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+.
The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia.
After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues. Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types. It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules. In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+. The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia. After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.
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Punchihewa, Chandanamalie. "DNA and DNA-Interacting Proteins as Anticancer Drug Targets". Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/194379.
Texto completo da fonteResumo:
DNA is both the oldest and newest of targets for cancer therapy. While it is already being targeted by many anticancer drugs in the clinic, the development of sequence-specific DNA binders has brought it back to the limelight as a valuable anticancer drug target.My studies on DNA interacting agents was initiated with the DNA intercalator campotothecin, and also included topoisomerase I enzyme. I have evaluated the structure of topoisomerase I C-terminal domain that consists of the active site tyrosine. My data indicate that this domain exists in a molten globule conformation with a fluctuating tertiary structure. These fluctuations are suggested to be important in interaction with the topoisomerase I core domain and DNA. I have also evaluated the DNA interactions of the camptothecin analogue homocamptothecin and have determined that homocamptothecin intercalate with DNA in the absence of topoisomerase I, and that such intercalation results in its lactone stabilization. Subsequently, the mechanism of topoisomerase I mediated inhibition of HIF-1 by camptothecin was explored. I have shown that camptothecin stimulate topoisomerase I cleavage complex formation in the HIF-1 binding site, which is suggested to prevent the DNA binding of HIF-1.The second part of this study was focused on understanding the mechanism of action of another DNA binder, XR5944. Designed as a dual topoisomerase inhibitor, XR5944 was subsequently shown to have a different mechanism of action - inhibition of trancription. The NMR structural analysis, in our lab, of the drug-DNA complex showed that XR5944 bis-intercalate with DNA, while binding in the DNA major groove. Driven by these combined interaction modes, XR5944 is shown to inhibit the DNA binding and the subsequent transcriptional activity of specific transcription factors such as estrogen receptors and AP-1, which are overexpressed in certain cancers.Finally, I have analyzed G-quadruplex structures formed by telomeric DNA. The formation and stabilization of DNA G-quadruplexes in the human telomeric sequence have been shown to inhibit the activity of telomerase. Thus the telomeric DNA G-quadruplex has been considered as an attractive anticancer drug target. Telomeric DNA forms multiple G-quadruplex conformations, and my data reveal the conformations of the major G-quadruplexes formed by human telomeres.
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Heyenga, Gerard. "Tissue culture of Podophyllum hexandrum and production of anticancer ligands". Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235985.
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