Nouveaux Inhibite Nanomolaires du Protéasome en Chimiothérapie du Cancer. Salinosporamides et analogues – proteasome

The goal of this investigation is to find new anticancer therapies and the success of Bortezomib in the treatment of multiple myeloma provided evidence that proteasome inhibitors can be effective clinically. Salinosporamide A, recently isolated from marine sediments, is a novel potent proteasome inhibitor (nM). To explore the potentiality of this original cis-fused pyrrolidinone-b-lactone system, we defined a synthetic program involving two unusual, concise and versatile strategies. The integrity of cellular processes depends upon the proper balance of different proteins. Among the possible ways to control the activities of such molecules, controlling protein half-life itself by destruction has emerged as a major cellular regulatory mechanism. The ubiquitin/proteasome-dependent protein degradation pathway is a central player in this degradation process. It occupies an essential role in cell growth and maintenance in both up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Sensibility of cancer cells to proteasome inhibition via disruption or proliferation and/or induction of apoptosis suggest that proteasome inhibitors could be very attractive as novel anticancer drugs. Thus far, Bortezomib, a highly selective reversible inhibitor of the 26S proteasome, is the first treatment in more than a decade to be FDA (in May 2003) and European Union (in April 2004) approved for patients with Multiple Myeloma. Promising clinical investigations are under way to evaluate this drug in other cancer types. This boronic acid dipeptide exhibits proteasome inhibition via a pseudo-covalent complex formation with N-terminal threonin on proteasome 20S. Recently (2003), Fenical reported on the isolation of a highly active metabolite, termed Salinosporamide A. Salinosporamide A displays remarkable in vitro cytotoxicity (IC50 of approximatively 10nM) and its activity results from potent inhibition of the 20S proteasome. In very recent preclinical studies (June 2005), it was shown that this compound (also termed NPI-002) blocks a wider range of proteasome activities than bortezomib, works at lower doses, appears to kill resistant cells and to be less toxic to normal cells. Furthermore, NPI-0052 can be given orally (Bortezomib is currently given by intravenous infusion). Structurally, Salinosporamide A encompasses an original b-lactone-g-lactam bicyclic ring system with vicinal quaternary centres at the ring juncture. The b-lactone is recognized as a key pharmacophore (it forms a covalent adduct with the N-terminal Thr on proteasome 20S). Salinosporamide A seems to be a good lead for proteasome inhibition and cancer therapy. At this writing, there are two recent reported total synthesis of Salinosporamide A (Corey 2004, Danishefsky 2005). In the research program proposed here, our group was aimed at gaining a new access to this molecule capable of providing substantial quantities. The developed strategy should be concise, specially adapted to the formation of the C3 and C4 consecutive quaternary centres, scaleable and versatile (for analogues synthesis). We proposed two strategically different syntheses of Salinosporamide A, based on original key steps and sequences. These two syntheses could conduct to analogues with quite different structures. This project will involve an innovative associated methodology work to finalize the synthesis, owing that formation of two contiguous quaternary centres remains a real challenge. In the first synthetic approach, we initially focused on solving the two quaternary centres installation; for this purpose, we will privilege the a-alkylation of a bicyclic ketone derivative in which the exo face attack is favoured. This method must be associated to an efficient oxygen bridge cleavage of the oxabicyclic derivative by reaction of nucleophilic agents. Finally, total synthesis of Salinosporamide A will be achieved using a proline-catalyzed aldol reaction for stereosele.