Cancer cell esterases are often overexpressed and some have chiral specificities different from those of corresponding normal cells. Carboxylesterases in particular are known to be overexpressed in several cancers. Additionally, cancer cells often exhibit high levels of intrinsic oxidative stress that is required for survival and an aggressive phenotype. We hypothesized that these 2 characteristics of cancer cells could be exploited to aid in the detection and treatment of prostate cancer. We have developed a fluorogenic ester probe that is activated by carboxylesterase to help distinguish tumorigenic cells from nontumorigenic prostate cells. Ester prodrugs have the same activation mechanism and have been thought to be a promising approach in cancer therapy. Prodrugs are inactive drugs that can be selectively activated by a specific enzyme. We have developed a chiral ester prodrug strategy using native polyacrylamide gel electrophoresis (n-PAGE) and proteomic methods to compare and identify the esterase profiles of several tumorigenic and nontumorigenic prostate cell lines. Our results showed that cell lysates from LNCaP, DU 145, and PC3 prostate cancer cell lines exhibit differential esterase activity compared with non-tumorigenic RWPE-1 prostate cell lysates when incubated with α- naphthyl acetate or α-naphthyl N-acetyl-alaninate ester substrates and a diazonium salt. We have identified oxidized protein hydrolase (OPH), a serine esterase/protease that catalyzes the removal of N-acylated residues from proteins, to be differentially expressed between some tumorigenic and nontumorigenic prostate cell lines. OPH was found to have high hydrolytic activity towards the S-isomer of α-naphthyl N-acetylalaninate (S-ANAA) chiral ester. LNCaP lysates incubated with N-acetyl-alanyl-p-nitroanilide, a known OPH substrate, had twofold higher OPH activity compared with RWPE-1 lysates. We have also developed and tested novel glutathione depleting prodrugs modeled after S-ANAA that increase oxidative stress and induced apoptosis in tumorigenic prostate cells with little effect on nontumorigenic RWPE-1 cells. These results suggest that ester molecular beacon probes and ester prodrugs may be effective in identifying and treating prostate cancer tumors that overexpress esterases with little effect on normal prostate cells.

Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly disease. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes is discussed in the first chapter of the dissertation. Convenient synthetic approaches to 3-aryl-4(1H)-quinolones via metal-catalyzed and metal-free arylation of β-keto carbonyl compounds is addressed in Chapter 2. A clean arylation protocol of ethyl acetoacetate was developed by using hypervalent diaryl iodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts varying in sterics and electronics was examined. This method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development. Additionally, a first gram scale synthesis of ELQ-300 and its structurally related 4(1H)-quinolone P4Q-391 using operationally simple and highly yielding metal-catalyzed conditions have been shown. Despite of 3-aryl-4(1H)-quinolone chemotypes displaying potent antimalarial activities against Plasmodium species in vitro and in vivo, their development is also associated with risks. 4(1H)-quinolones are known to be poorly soluble and thus represent challenging drug candidates for pharmacokinetic and bioavailability reasons. Disrupting of molecular crystal packing and prodrug approaches were employed to overcome solubility and bioavailability issues in current series. Quantum mechanics torsion profile calculations, 13C T1 spin-lattice relaxation experiments as well as X-ray studies were conducted with the objective to determine possible effects improving key physicochemical properties such as solubility and stability. As a backup strategy, a prodrug approach was developed enabling the 4(1H)-quinolone scaffold to be functionalized at the quinolone's oxygen. In order to avoid any enzymatic dependences, an approach was developed in which the prodrug moiety was removed via a pH-triggered decay. Additionally, phosphate prodrugs regenerating the active compound via extrahepatic enzymes such as the ubiquitous alkaline phosphatase were investigated. The development of orally bioavailable prodrugs enabled an advance overcoming in vivo efficacy limitations and has been confirmed by pharmacokinetic profiling studies. The herein presented approaches present viable options for any pyridone quinolone antimalarial chemotype which are currently studied.

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 study / undecenol 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.

This study presents synthetic studies on camptothecin, a potent antitumor agent in order to improve its stability and solubility without reducing its activity. The study consists of the modification of camptothecin at 20-OH position a new strategy for the targeted and controlled release of the drug and modification at C-7 position to overcome the stability and solubility problems of the free drug. In the first part of the study, the 20-OH functional group of camptothecin was replaced with an unsymmetrical benzoin derivative that is able to release the drug under photolysis at 350 nm. The new prodrugs synthesized possessed higher stability than the camptothecin itself. The in vitro irradiation of the prodrugs at 350 nm was satisfactory without any decomposition of the active substance. The second part of the study comprises the studies on the modification of the 7th position of camptothecin, which is the most suitable position for the modification. In this part of the study, 7-amino and silyl substituted camptothecins were synthesized.Combination of camptothecin with some other drugs such as cisplatin was also investigated in this study. The synthetic efforts showed that the reactions are very promising and the combination studies can be studied as a major subject in the future.

No description available.

Yes / There is a need to understand the nature of aggregation of cyclodextrins (CDs) with guest molecules in increasingly complex formulation systems. To this end an innovative application of Taylor dispersion analysis (TDA) and comparison with dynamic light scattering (DLS) have been carried out to probe the nature of ICT01-2588 (ICT-2588), a novel tumor-targeted vascular disrupting agent, in solvents including a potential buffered formulation containing 10% hydroxypropyl-β-cyclodextrin. The two hydrodynamic sizing techniques give measurement responses are that fundamentally different for aggregated solutions containing the target molecule, and the benefits of using TDA in conjunction with DLS are that systems are characterised through measurement of both mass- and z-average hydrodynamic radii. Whereas DLS measurements primarily resolve the large aggregates of ICT01-2588 in its formulation medium, methodology for TDA is described to determine the size and notably to quantify the proportion of monomers in the presence of large aggregates, and at the same time measure the formulation viscosity. Interestingly TDA and DLS have also distinguished between aggregate profiles formed using HP-β-CD samples from different suppliers. The approach is expected to be widely applicable to this important class of drug formulations where drug solubility is enhanced by cyclodextrin and other excipients.

no / The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.

No description available.

No description available.

Ce doctorat a permis la conception de nouvelles molécules destinées aux développements de futurs produits phytosanitaires. Tout d’abord, la synthèse d’alpha,alpha-difluoro-beta-hydroxy cétones a été réalisée. Motif déjà reconnu dans le domaine pharmaceutique, nous voulions étendre son champ d’application à l’agrochimie. Une série de composés possédant une activité biologique en tant qu’agonistes des récepteurs GABA a été synthétisée. Ils ont été obtenus à l’issu d’une synthèse convergente nécessitant une réaction de couplage entre un aldéhyde aromatique et un intermédiaire alpha,alpha-difluoro-beta-trifluoromethyldihydroxy cétone. L’analyse biologique de nos produits a fait ressortir un type de famille spécifique. Une approche prodrug a débuté afin d’en affiner la structure et d’en faire ressortir un hit. Dans un second temps, le développement d’une série de quinoléines substituées par des groupements fluorés en position 2 et 4 a été conduit. Ces molécules peu décrites dans la littérature fûrent synthétisées dans des conditions douces avec de bons rendements et une complète régiosélectivité, inspirée par les réactions de Combes et de Meth-Cohn utilisant un Réactif Fluoroalkyl Amine (FARs). La post-fonctionnalisation en position 3 et 8 a permis l’exemplification de ces composés. Une étude physico-chimique réalisée sur une série homogène a apporté des informations complémentaires sur leurs propriétés électroniques. Bien qu’aucune molécule n’ait montré d’activité biologique, nous avons pu lors de ce projet réaliser la synthèse de nouvelles quinoléines et évaluer des FARs dans la synthèse de molécules inconnues de la littérature jusqu’à ce jour. / This PhD thesis allowed the conception of new molecules for the development of novel phytosanitary ingredients. First, the synthesis of alpha,alpha-difluoro-betahydroxy ketones was performed. Since this motif is already known in the pharmaceutical field, we decided to extend their application to the agrochemical field. A series of compounds with biological activities as GABA agonist receptors was synthesized. They were obtained by a convergent method after a coupling reaction between benzaldehydes and alpha,alpha-difluoro-beta-trifluoromethyldihydroxy ketone intermediates. Biological analysis highlighted a specific family of compounds. A prodrug approach was applied to tune the structure and allowed the discovery of a hit. Second, the development of a series of 2,4-(fluoroalkyl)-substituted quinoline derivatives was conducted. Scarcely described in literature, these molecules were obtained under smooth conditions, with good yields and a complete regioselectivity, inspired by Combes and Meth- Cohn reactions using Fluoroalkyl Amino Reagents (FARs). Post-functionalization in position 3 and 8 allowed us to increase the scope of the reaction. A physico-chemical study gave complementary informations on their electronical properties. Although none of these molecules have shown biological activity, we have during this project realized the synthesis of new quinolines and evaluated the use of FARs in the synthesis of unknown fluorinated molecules.