Abstract EN:

Resistance to current treatments of cancer encourages to find nex therapeutic targets. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates the folding and maintains the proper conformation of many client proteins associated with all six hallmarks of cancer. Consequently, HSP90 has become an exciting new target in cancer drug discovery because the inhibition of its ATP activité leads to depletion of these client proteins via the ubiquitin-proteasome pathway. The N-terminal ATP binding domain was shown to bind geldanamycin, radicicol and purines. Novobiocin, a coumarin-containing DNA gyrase inhibitor, binds to hsp90 at the C-terminal nucleotide-binding region. This thesis aimed at the identification of novel inhibitors based on non-sugar coumarin scaffold. In order to establish a SAR profile on this HSP90 targeting agent,we have synthetized a serie of novobiocin analogs including those that connect the substitued coumarin ring to the aryl moiety through an amide-, a retro amide- and an alkyne-linkage. Among the synthetic derivatives, one compound showed to be more efficient than novobiocin. The synthesis of new hydrosoluble analogs is currently underway.