Development of XIAP Antagonists Based On De Novo 8,5-Fused Bicyclic Lactams.

ABSTRACT: In order to develop original water soluble antagonists of X-linked inhibitor of apoptosis protein (XIAP), a novel bicyclic scaffold was designed based on 8,5-fused bicyclic lactam. During its preparation, a spontaneous rearrangement from 8,5- to 7,5-fused bicyclic lactam was observed and confirmed by MS and NMR analyses, in particular the HMBC spectra. DFT calculations were performed to understand the corresponding mechanism. It was finally prevented through changing the reaction order in the synthesis route and a Smac mimetic with this core structure, ZJ-1 was successfully obtained. The structure of this new bicyclic scaffold was well confirmed by HRMS and NMR (¹H, ¹³C, NOESY) analyses. ZJ-1 presented in addition a binding affinity to XIAP-BIR3, nearly

SUBMITTER: Sheng ZJ 

PROVIDER: S-EPMC6331714 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature