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CC BY 4.0 · Pharmaceutical Fronts 2020; 02(03): e143-e149
DOI: 10.1055/s-0040-1722543
Short Communication

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

Qingwei Zhang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China
,
Guili Xu
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China
2   College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, PR China
,
Ya Bao
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China
2   College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, PR China
,
Minru Jiao
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China
,
Jianqi Li
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, P. R. China
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Abstract

A series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

Keywords

c-Met/HDAC inhibitor - dual inhibitor - hybrid - antitumor drugs - multipharmacology


Publication History

Received: 12 August 2020

Accepted: 24 September 2020

Article published online:
16 December 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
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