Synthesis And Structural Optimization Of Hsp90 Inhibitors For

Hsp90 is an important molecular chaperone that helps proper folding of its client proteins under stress. For many oncoprotein in cancer cells are client proteins, the inhibition of Hsp90’s chaperone activity in cancer cell would lead to the ubiquination and degeneration of a number of oncoprotein, and therefore so Hsp90 is a promising target for cancer therapy.In this thesis, we describe the synthesis and biological evaluation of a library of Hsp90 inhibitors that was designed based on the early findings in our group.The target compunds were synthesized following a newly established convergent approach, and evaluated for their in vitro acticancer actibities in tumor cell models HCT116B, GC823, A375, MCF7and Mia.7 active compounds were found and then subjected to a polarized fluorescence assayto determine their Hsp90 affinity. The results in dicated that all these compound competitively bind to the ATP-binding site of Hsp90,with IC50s ranging from 6.04-10.24×10-8M.Preliminary structure-activity relationship was proposed based on these data.