NATURAL AND SEMISYNTHETIC AZAPHILONES AS A NEW SCAFFOLD FOR Hsp90 INHIBITORS

Interest in the heat shock protein 90 (Hsp90) molecular chaperone as a therapeutic target is related to its central role in correct folding and stabilization of proteins involved in malignant behaviour and tumour progression. Several Hsp90 client proteins are part of critical processes including cell-cycle regulation and apoptosis. HSPs are often overexpressed in tumor cells, and this supports their ability to survive under unfavorable stress conditions. Thus, targeting Hsp90 may have the potential advantage of simultaneously blocking multiple oncogenic pathways. In this work a series of mould metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the Hsp90. In particular, bulgarialactone B2 was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. The natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. In vivo activity of 2 against an ascitic ovarian carcinoma xenograft supports the therapeutic potential of this novel series of Hsp90 inhibitors