Open AccessDevelopment of XIAP Antagonists Based On De Novo 8,5‐Fused Bicyclic Lactams
Author(s) -
Sheng Zhaojun J.,
Shi Yiming M.,
Xu Ximing,
Bellynck Sébastien,
Zhang Kun,
Du Zhiyun Y.,
Xu Xuetao,
Maurel François,
Dong ChangZhi
Publication year - 2019
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201800260
Subject(s) - bicyclic molecule , xiap , chemistry , stereochemistry , lactam , combinatorial chemistry , apoptosis , biochemistry , programmed cell death , caspase
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 ( 1 H, 13 C, NOESY) analyses. ZJ‐1 presented in addition a binding affinity to XIAP‐BIR3, nearly 6 times better than that of AVPI, similar to the reported SM‐128 in an in vitro fluorescence polarization (FP) assay. This preliminary result suggests that this new bicyclic scaffold could be very attractive in the development of novel anticancer agents targeting XIAP.