3,4-dihydropyrimidin-2(1H)-one as a useful scaffold for Hsp90 C-terminal inhibition

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays a crucial role in stabilizing and activating more than 200 “client proteins”, many of which are involved in signal transduction, cell cycle regulation and apoptosis [1]. Therefore a considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90 has aroused. Recently several N-terminal Hsp90 inhibitors have been identified and are currently in clinical trials, while only few C-terminal inhibitors have been reported. Here we describe the synthesis of 3,4- dihydropyrimidin-2(1H)-ones performed through a microwave-assisted Biginelli reaction [2]. These compounds have been extensively evaluated for their biological activity using several assays including surface plasmon resonance (SPR), inhibition of cell proliferation and cell cycle arrest, depletion of client proteins. From these studies a new promising molecule has emerged. In order to identify the binding site on the target protein we have performed limited proteolysis experiments which suggested the interaction of the compound with the C-terminal domain of Hsp90 and a binding mode has been proposed by molecular docking.