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Development of XIAP Antagonists Based On De Novo 8,5-Fused Bicyclic Lactams |
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| Authors: | Dr Zhaojun J Sheng Dr Yiming M Shi Ximing Xu Sébastien Bellynck Kun Zhang Prof Zhiyun Y Du Xuetao Xu Prof François Maurel Prof Chang-Zhi Dong |
| Institution: | 1. Interfaces, Traitements, Organisation et Dynamique des Systemes (ITODYS) UMR 7086 CNRS, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
School of Chemical Engineering and Light Industry Institute of Natural Medicine and Green Chemistry, Guangdong University of Technology, 510006 Guangzhou, China School of Chemical and Environment Engineering, Wuyi University, 529020 Jiangmen, China;2. Interfaces, Traitements, Organisation et Dynamique des Systemes (ITODYS) UMR 7086 CNRS, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France;3. School of Electrical and Information Engineering Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, 213001 Changzhou, China;4. School of Chemical Engineering and Light Industry Institute of Natural Medicine and Green Chemistry, Guangdong University of Technology, 510006 Guangzhou, China School of Chemical and Environment Engineering, Wuyi University, 529020 Jiangmen, China;5. School of Chemical Engineering and Light Industry Institute of Natural Medicine and Green Chemistry, Guangdong University of Technology, 510006 Guangzhou, China;6. School of Chemical and Environment Engineering, Wuyi University, 529020 Jiangmen, China |
| 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 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. |
| Keywords: | anticancer drugs lactams Smac mimetics spontaneous rearrangement XIAP antagonists |