Synthesis, physicochemical and pharmacokinetic studies of potential prodrugs of β-L-2'-deoxycytidine, a selective and specific anti-HBV agent

β-L-2′-Deoxycytidine (β-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well as N4-derivatization with an N,N-(dimethyl-amino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, β-L-dC. Presented in part at the 14th International Conference on Antiviral Research, Seattle, Washington, USA, 8–13 April 2001. Antiviral Reseach 2001; 50:A79

Synthèse et étude de C-nucléosides à visée anti-hépatite C

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Synthèse et Etude d'Analogues Peptidiques en tant qu'Inhibiteurs de Fusion du VIH

Depuis la découverte du Virus de l'Immunodéficience Humaine (VIH) au début des années 80, la recherche de nouvelles molécules anti-VIH demeure un challenge important pour la communauté scientifique. Les effets secondaires liés à l'usage d'inhibiteurs de la réplication virale, la découverte des récepteurs et la compréhension du mécanisme d'entrée du virus dans la cellule hôte ont encouragé la recherche sur de nouveaux inhibiteurs ciblant l'entrée virale. A ce jour, l'Enfuvirtide est le seul inhibiteur d'entrée approuvé en tant qu'inhibiteur de fusion. Bien que ce composé soit un antiviral puissant, il présente néanmoins de sérieuses limitations, son mode d'administration (injection sous cutanée deux fois par jour) et l'émergence de résistances, le classent en agent rétroviral de seconde classe. Une approche alternative est la génération de D-peptides inhibiteurs de fusion, résistants aux protéases et prometteurs pour le développement et l'identification d'une nouvelle classe de médicaments anti-VIH. Basée sur cette dernière approche, cette thèse est consacrée à la synthèse et à l'étude d'analogues peptidiques en tant qu'inhibiteurs de fusion du VIH. Tout d'abord, des études de modélisation associées à la synthèse d'analogues peptidiques ont permis de mettre en évidence et de comprendre les caractéristiques essentielles responsables de l'activité des D-peptides. Ensuite, des études de relations structure-activité, à partir de séquences modifiées, ont conduit à l'obtention de nouveaux analogues peptidiques inhibiteurs de fusion actifs. Enfin, dans le but de réduire la nature peptidique et par conséquent d'améliorer les propriétés pharmaceutiques, des macrocycles peptidiques ont été conçus, et une nouvelle stratégie de synthèse de peptides cycliques a été développée.Since the discovery of the Human Immunodeficiency Virus (HIV) at the beginning of the 1980's, the search for new anti-HIV molecules remains an important challenge for the scientific community. Secondary effects associated with viral replication inhibitors, the discovery of receptors and the understanding of the mechanism of the viral entry makes HIV viral entry one of the most promising target for HIV drug development. To date, Enfurvitide is the only approved entry inhibitor as HIV fusion inhibitor. Although highly effective, Enfurvirtide has several serious limitations including high dosing requirements, the administration by injection, and the emergence of resistant strains. An alternative approach that has shown considerable potential is the generation of new D-peptides HIV fusion inhibitors expected to be resistant to proteolytic degradation and useful for the development and the identification of a new class of anti-HIV drugs with improv ed bioavailability.Based on this approach, the present work is dedicated to the synthesis and the study of peptide analogs as HIV fusion inhibitors. First, modeling studies and the synthesis of peptide analogs were devoted to point out and to understand the key elements responsible for the activity of the reference D-peptides. Then, structure activity relationship studies based on different modifications sequences led to the discovery of active peptide analogues as HIV fusion inhibitors. In another approach, in order to decrease peptide nature and consequently to improve the pharmaceutical properties, reduced cyclic peptides were designed. Finally, a novel strategy for cyclic peptide synthesis was developed.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states

International audienceA 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase

Synthesis of Unnatural Phosphonosugar Analogues.

International audienceThe first synthesis of new cyclic phosphonates (phostones), analogues of pentafuranoses containing a phosphorus atom in place of the anomeric carbon in the deoxyribose and deoxyxylose series, is described. Two methods, of respectively six and seven steps, were developed in parallel, and each gave the racemic phosphonosugars in good yields. Compounds analogous to the alpha and beta anomers were isolated and fully characterized by NMR spectroscopy

Synthesis of unnatural 2- and 3-deoxyfuranose analogues.

International audienceThis Letter describes the synthesis of two racemic analogues of unnatural 3′-deoxy and 2′-deoxy sugars, where a phosphorus atom replaces the carbon atom in the 2′- or 3′-position. Two methods of four- and 5-steps were developed affording these new unnatural sugar analogues