Etude de systèmes moléculaires programmés pour la libération sélective d'agents anticancéreux

Le problème majeur de la chimiothérapie anticancéreuse conventionnelle réside dans la faible sélectivité des agents cytotoxiques vis-à-vis des tumeurs, entrainant de sévères effets secondaires et un phénomène de résistance pleïotropique. L'utilisation de prodrogues, activées sélectivement au niveau de la tumeur par la b-glucuronidase, au cours d'un protocole ADEPT (Antibody Directed Enzyme Prodrug Therapy) ou PMT (Prodrug Mono Therapy), permet de limiter ce problème. Ainsi, une prodrogue glucuronylée de la doxorubicine, HMR 1826, s'est révélée être plus efficace que l'agent actif correspondant au cours du traitement de nombreuses tumeurs in vivo. Ces travaux de thèse s'inscrivent dans la continuité de ces résultats avec pour objectif d'améliorer le concept des prodrogues glucuronylées. Dans une première partie, ce concept a été appliqué aux HDACi avec la synthèse et l'évaluation biologique d'une prodrogue glucuronylée de MS-275. La deuxième partie est consacrée à l'étude d'une nouvelle structure dendritique auto-immolable permettant de vectoriser deux agents anticancéreux de même nature ou de nature différente et d'assurer leur libération après une seule hydrolyse enzymatique. Les études biologiques ont permis de valider le potentiel de cette approche. Ce concept a été étendu aux dimères de cyclodextrines, pour permettre le transport de l'agent actif sans liaison covalente. Enfin, la troisième partie du manuscrit est consacrée à l'étude d'un système permettant le ciblage de deux particularités tumorales spécifiques aux cellules et au microenvironnement.The major problem with conventional cancer chemotherapy is the low selectivity of cytotoxic agents against tumors, causing severe side effects and pleiotropic resistance. To overcome these drawbacks, prodrugs have been developed to be selectively activated at the tumor site by b-glucuronidase during an ADEPT (Antibody Directed Enzyme Prodrug Therapy) or a PMT (Prodrug Mono Therapy) protocol. Within this framework, the glucuronylated prodrug of doxorubicin, HMR 1826, has demonstrated superior efficiency during the treatment of various human xenografs in mice compared to standard chemotherapy. In the course on this PhD new approaches have been developed to improve the scope of glucuronylated prodrugs. The first part of this work describes the synthesis and biological studies for a glucuronylated prodrug of MS-275. The second part is devoted to the study of a new self-immolative dendritic structure designed to target two cytotoxic molecules, even different, and to release the drugs after a single enzymatic hydrolysis. Biological studies have validated the potential of this approach. This concept has been extended to cyclodextrin dimers, to allow the transport of active agent without covalent bonds. Finally, the last approach of the manuscript is devoted to the study of a system suitable for targeting cells and micro-environment specificities of the tumor.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Synthèse d'analogues d'inhibiteurs d'histone désacétylases

POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Synthèse d'édifices supramoléculaires dédiés à la vectorisation d'agents thérapeutiques

La vectorisation d agents thérapeutiques vers leur zone d action est un axe de recherche important et plus particulièrement dans le domaine du cancer. Il est important de concevoir des systèmes moléculaires capables de transporter des drogues de façon inoffensive vis-à-vis des tissus sains et de déclencher l activation de l agent antitumoral uniquement lorsque la tumeur est détectée. Les travaux présentés dans ce mémoire de thèse portent sur l emploi de cyclodextrines dans la conception d édifices supramoléculaires pour la vectorisation d agents thérapeutiques. Les cyclodextrines peuvent solubiliser un principe actif, modifier sa disponibilité en interagissant avec les membranes cellulaires, améliorer sa pharmacocinétique ou encore cibler son action thérapeutique. Un édifice moléculaire basé sur les cyclodextrines et dédié à la vectorisation peut être envisagé autour de trois parties : la cyclodextrine, un espaceur et le vecteur. Une première partie de ce travail concerne le choix de l espaceur, car il doit apporter au système un maximum d efficacité, que ce soit en complexation, en solubilisation ou en vectorisation. Concernant la vectorisation, le concept des prodrogues auto-immolables a été largement étudié. Notre second objectif est d associer le concept des cyclodextrines avec celui des prodrogues pour concevoir de nouveaux édifices supramoléculaires dédiés à la vectorisation de drogues. La synthèse de dimères de cyclodextrines auto-immolables sera présentée ainsi que les premiers résultats concernant le potentiel de ces édifices dans la capture, la solubilisation et la vectorisation de droguesSite-specific delivery of clinically used drugs is an important aspect of research, particularly in the field of cancer treatment. It s important to design molecular systems capable of transporting drugs in an innocuous fashion for healthy tissues and with the activation of the therapeutic agent only at the tumour site. The presented work consists of the use of cyclodextrins in the conception of supramoleculars structures for the targeting of therapeutics agents. Cyclodextrins have been known to solubilize active compounds, enhance their bioavailability by interactions with the cell surface, improve their pharmacokinetic profile and drug targeting. Such a system can be separated into three distinct portions namely: the cyclodextrin, a spacer and a ligand. The first objective of this work was the choice of the spacer arm because it should result in an efficient system capable of optimal complexation, solubilization and vectorization. In the field of drug-targeting, the concept of self-immolative prodrugs has been widely studied. Our main objective was to associate the advantages of cyclodextrins with that of prodrugs in order to create new supramoleculars structures dedicated to drug targeting. The synthesis of these self-immolative cyclodextrins dimers shall be detailed, as well as the preliminary results concerning the capacity of these structures to capture, solubilize and vectorize an antitumorous drugPOITIERS-BU Sciences (861942102) / SudocSudocFranceF

A self-immolative dendritic glucuronide prodrug of doxorubicin

International audienceThe first self-immolative dendritic glucuronide prodrug of doxorubicin was studied with the aim to target beta-glucuronidase overexpressed in the microenvironment of numerous tumors. This compound includes a chemical amplifier programmed to release two molecules of doxorubicin after a single enzymatic activation step. Upon beta-glucuronidase activation, the dendritic prodrug was twice more toxic than its monomeric counterpart against H661 lung cancer cell

The Lossen rearrangement from free hydroxamic acids

International audienceThe Lossen rearrangement, that allows the conversion of hydroxamic acids into isocyanates, was discovered almost 150 years ago. For more than a century, this transformation was supposed to occur exclusively in the presence of stoichiometric amounts of activating reagents devoted to promoting the dehydration of primary hydroxamic acids. Very recently, it was demonstrated that the Lossen rearrangement can take place directly from free hydroxamic acids offering a renewal of interest for such a reaction. This short review summarizes advances in this field by describing successively the metal-assisted, the self-propagative and the promoted self-propagative Lossen rearrangement with a special emphasis on their mechanisms

beta-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: An update

International audienceThe design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of beta-glucuronidase-responsive albumin binding prodrugs

A dendritic β-galactosidase-responsive folate-monomethylauristatin E conjugate.

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The First Generation of β-Galactosidase-Responsive Prodrugs Designed for the Selective Treatment of Solid Tumors in Prodrug Monotherapy†

International audienceGalactoside prodrugs have been designed that can be selectively activated by lysosomal β-galactosidase located inside cancer cells expressing a specific tumor-associated receptor. This efficient enzymatic process triggers a potent cytotoxic effect, releasing the potent antimitotic agent MMAE and allowing the destruction of both receptor-positive and surrounding receptor-negative tumor cells

A mechanically interlocked molecular system programmed for the delivery of an anticancer drug

The development of mechanically interlocked molecular systems programmed to operate autonomously in biological environments is an emerging field of research with potential medicinal applications. Within this framework, functional rotaxane- and pseudorotaxane-based architectures are starting to attract interest for the delivery of anticancer drugs, with the ultimate goal to improve the efficiency of cancer chemotherapy. Here, we report an enzyme-sensitive [2]-rotaxane designed to release a potent anticancer drug within tumor cells. The molecular device includes a protective ring that prevents the premature liberation of the drug in plasma. However, once located inside cancer cells the [2]-rotaxane leads to the release of the drug through the controlled disassembly of the mechanically interlocked components, in response to a determined sequence of two distinct enzymatic activations. Furthermore, in vitro biological evaluations reveal that this biocompatible functional system exhibits a noticeable level of selectivity for cancer cells overexpressing β-galactosidas

Synthesis and Antitumor Efficacy of a β-Glucuronidase-Responsive Albumin-Binding Prodrug of Doxorubicin

In this paper we describe the synthesis and biological evaluation of the first β-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug