Discovery of novel 9H-purin derivatives as dual inhibitors of HDAC1 and CDK2

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2136-2140. doi: 10.1016/j.bmcl.2019.06.059.

Yu Yu ¹, Dongzhi Ran ¹, Junhao Jiang ¹, Tao Pan ², Yanrong Dan ², Qiang Tang ¹, Wei Li ¹, Lin Zhang ², LinLing Gan ², Zongjie Gan ³

Affiliations

1 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China; Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China.
2 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China.
3 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China; Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: gzj@cqmu.edu.cn.

PMID: 31272794 DOI: 10.1016/j.bmcl.2019.06.059

Abstract

HDAC and CDK inhibitors have been demonstrated to be synergistically in suppressing Cancer cell proliferation and inducing Apoptosis. In this work, we incorporated the pharmacophore groups of HDACs and CDKs inhibitors into one molecule to design and synthesize a series of purin derivatives as HDAC/CDK dual inhibitors. The lead compound 6d, showing good HDAC1 and CDK2 inhibitory activity with IC₅₀ values of 5.8 and 56 nM, respectively, exhibited attractive potency against several Cancer cell lines in vitro. This work may lead to the discovery of a novel scaffold andpotentialdual HDAC/CDK inhibitors.

Keywords

Antitumor; CDKs; Dual inhibitors; HDACs; Purin.

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