Samir Messaoudi

Research - Samir - Members - Publications


The Glycochemsitry topic deals with the use transition metal-catalyzed approaches to explore new ways to functionalize glycosides. The chemistry in this proposal involves the development of a series of processes concerning N-, S- , O- or C-glycosidic bonds functionalization under transition metal catalysis.
Based on the successful outcome of this project, an unlimited number of organic transformations will be possible in the future, and the development of such new sustainable methodologies will make a tremendous impact into routine organic synthesis of glycoconjugates and into selective late-stage modification of pharmaceuticals. This conceptually novel approach would provide chemists in both the academic and industrial worlds with new disconnection strategies that give access to molecules with original structures and properties in a simple, efficient, and ecological manner.


Hsp90 is an emerging therapeutic target of interest for the treatment of cancer and other diseases. As a chaperone protein, hsp90 is essential to ensure the correct conformation, activity, intracellular localization and proteolytic turnover of a range of proteins that are involved in cell growth, differentiation and survival.The hsp90 protein function may be inhibited by molecules competing with ATP binding, thereby freezing the chaperone cycle, which in turn decreases the affinity of hsp90 for client proteins and leads to proteasome-mediated oncogenic client protein degradation. Several structurally distinct hsp90 inhibitors, as single agents or in combination with other cancer drugs, are currently being evaluated for anticancer activity in numerous Phase II and several Phase III clinical trials.

A few years ago, a hypothesis had suggested the presence of two ATP binding sites on the hsp90 protein. The N-terminal ATP-binding pocket of hsp90 is the binding site of the structurally unrelated natural products geldanamycin (GA) and radicicol (RD). The C-terminal domain has been implicated biochemically as the site of a possible second, cryptic ATP-binding site on hsp90. Its contribution to the overall regulation of chaperone function is not clear, but the antibiotic novobiocin has been reported to bind this site and alter the conformation of the chaperone. Although it binds with poor affinity, Nvb destabilizes hsp90 client proteins at high concentrations ( 700 microM). A better understanding of the role of this putative hsp90 C-domain site in regulating the function of the chaperone, as well as its potential as an anticancer drug target, requires further investigations. Advantages of HSP90 inhibitors that target the C-terminal domain (C-terminal inhibitors) include less robust activation of heat shock factor 1 (HSF1), which induces HSP90 transcription. Thus,the identification of more potent site-specific inhibitors is needed and has led the development of specific C-terminal hsp90 inhibitors as potential anticancer drug modalities.

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