Institut de Chimie et Biochimie Moléculaires et ... · Institut de Chimie et Biochimie...

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires SSyynntthhèèssee ddee MMoollééccuulleess dd’’IInnttéérrêêtt TThhéérraappeeuuttiiqquuee ((SSMMIITTHH)) Dr. Maurice MEDEBIELLE – Directeur de Recherche au CNRS – HDR

Synthèse de Molécules d’Intérêt Thérapeutique (SMITH) Tél : + 33 (0) 4 72 43 19 89/E-mail : medebiel@univ-lyon1.fr ICBMS UMR 5246 – Université Lyon 1 – CNRS – INSA - CPE Bâtiment CPE, 3ème étage - 43, Bd du 11 Novembre 1918 69622 VILLEURBANNE CEDEX - FRANCE

PhD PROPOSAL - OCTOBER 2010

“Methodologies to prepare difluoromethylene nitrogen, oxygen heterocycles and carbocyclic nucleosides – Potential kinase inhibitors, antiviral and antiplasmodial agents”

Fluorinated moieties can greatly modify the physico-chemical features and thus the biological properties of a molecule, and there is an increasing demand from the pharmaceutical to prepare such materials especially aromatic and heterocyclic derivatives because of their high value and pronouncing biological activity. For some years we have been interested to develop new synthetic approaches to prepare fluorinated organic molecules that may find applications as potential therapeutic agents. As part of a research program to use β-halogenodifluoromethylated enaminones as useful starting materials to prepare novel difluoromethylene-based oxygen and nitrogen heterocycles, we recently disclosed an interesting cyclization process to prepare unknown 5-halogeno-3,3-difluoro-2-aryl-6-arylaminodihydro-2H-pyran-4(3H)-ones A, 3,3-halogeno-5,5-difluoro-6-aryl-2-arylamino-2H-pyran-4(3H)-ones B, as well as 5-bromo-3,3-difluoro-2-aryl-2H-pyran-4(3H)-ones C (figure 1).

Some of these structures have been characterized by X-ray analyses. These novel cyclic oxygenated structures are of synthetic interest because they can be elaborated into more complex materials that may find applications as antiproliferative agents and kinase inhibitors, from the recent literature. One theme of the PhD proposal will then deal with a) a diastereoselective synthesis of structures A and B and extension to the synthesis of novel difluoromethylene carbohydrates/nucleosides as potential antivirals where the naturally ribofuranose skeleton will be replace by an hexofuranose analog (figure 2) and various piperidones/piperidines (see figure 1 for the extension),

b) chemical elaboration of structures A and B into fused nitrogen heterocycles using organometallic, radical or photochemical strategies (figure 3),

2

2

c) cross-coupling reactions of structures of type C to prepare a libraries of functionalized fluorinated pyrones, their piperidinones as well as piperidines analogues, structures that are of strong interest in medicinal chemistry (figure 4).

In a second area, closely related to our interest to prepare novel nucleosides (see figure 2), we would like to explore

pathways of modifying the natural nucleosidic skeleton using radical and anionic methodologies that we have been acquainted with in other structural contexts (figures 1 & 2). We are particularly interested in developing novel efficient syntheses of carbocyclic difluoromethylene nucleosides since a limited number of such molecules are known and their syntheses often require multisteps in rather unsatisfactory yields (see for example figure 5). In addition the antiviral and antitumoral biological data of these molecules have been rarely investigated!

Our goal will be then to propose new synthetic approaches with a limited number of steps (7-8 vs 14 as in figure 5) of the same family of CF2 carbocyclic nucleosides in addition to other analogs (several substitutions of the carbocyclic moiety). Extension to the synthesis of the C-Nucleosides that are potentially more stable (at the physiological pH and against metabolic processes) due to the presence of the C-C bond connection between the base and the sugar, in place of the usual C-N found in the natural nucleosides that is often associated with some degradation is also possible with our proposed methodology (figure 6). The biological evaluation of all the molecules presented here will be performed with existing collaborations locally (Faculté de Médecine, Université Lyon 1; NOVOCIB a biotechnology start-up) and internationally (Pharmaceutical Companies).

Figure 6

Figure 5