Synthesis of Reblastatin Autolytimycin Non-Benzoquinone Analogs: Potent Inhibitors of Heat Shock Protein 90 (Hsp90)

摘要

A full account of an asymmetric synthesis of reblastatin (>1), the first total synthesis of autolytimycin (>2) and related structural compounds is described. The syntheses expand the utility of a highly regio-and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (>6–9) of phenolic ansamycins. Ansamycin natural products and selected structural analogs were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (>1) and autolytimycin (>2) were shown to bind the Hsp90 protein with enhanced binding activity (~25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, >4), a geldanamycin (>3) derivative currently under evaluation for treatment of cancer (~100 nM).