Identification and synthesis of 3,4-isoxazolediamides as new class of Hsp90 inhibitors.

Abstract

Hsp90 is a protein of 90 kD that belongs to the family of the Heat Shock Proteins that are over expressed by the cells in response of a range of cellular stresses. Among the other functions, Hsp90 folds and maintains the proper conformation of a wide range of “client” or “substrate” proteins and hence acts as a molecular chaperone. It was observed that Hsp90 derived from tumor cells has particularly high ATPase activity and higher binding affinity for its inhibitors than the latent form in unstressed cells. In this context, Hsp90 has received significant recent attention as a therapeutic target for cancer treatment. Multiple research efforts have followed the initial discovery that two natural products [geldanamycin (GA) and radicicol] are potent inhibitors of Hsp90 therefore a plethora of compounds were planned and synthesized in the last times. Among these, resorcinolisoxazole inhibitors were demonstrated to possess a good solubility and in vivo potency so the lead of this class, VER-52296/NVP-AUY- 922, is now in Phase II clinical trials. As a part of our antitumor drug discovery project, we have recently undertaken a detailed structural investigation on 3,4-isoxazolediamides as new members of the above mentioned class of compounds (Figure 1). We mainly focused our attention on the C-4 position of the isoxazole scaffold where we found that compounds possessing a nitrogen atom directly attached to the heterocycle ring possess in vitro and in vivo Hsp90 inhibitory activity comparable and for some aspects better than the structurally related 4,5-diarylisoxazoles. In continuation of our efforts in search of potential antitumor agents, we planned to synthesize a new hits containing the 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]pyridine scaffold. In particular, one compound of this series has shown an important binding property and a notable antiproliferative activity