Facile Synthesis of a Library of 9-Alkyl-8-benzyl-9H-purin-6-ylamine Derivatives

摘要

The Hsp90 family of chaperones plays a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Occupancy of the ATP/ADP N-terminal pocket of Hsp90 by the natural products geldanamycin (GM) and radicicol (RD) interferes with the activity of the chaperone and causes the degradation of a subset of key signaling proteins dependent on Hsp90 function. The Her2 transmembrane tyrosine kinase is one of the most sensitive targets of the drugs. We have designed a novel Hsp90 inhibitor, PU3, the drugs. We have designed a novel Hsp90 inhibitor, PU3, a 9-alkyl-8-trimethoxybenzyl-purine, and demonstrated that this simple compound binds to Hsp90 and shares the important biological effects of GM and RD. PU3 is less potent, but it is a first-generation lead compound. It is likely that further modifications will yield derivatives with increased binding affinity and activity. Here, we describe the development of a facile synthetic route that we employed for the parallel synthesis of over 40 derivatives of the PU3 class.