Discovery and SAR analysis of 5-chloro-4-((substituted phenyl)amino)pyrimidine bearing histone deacetylase inhibitors |
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| Authors: | Lin Zhang Yiming Chen Fahui Li Lihui Zhang Jinhong Feng Lei Zhang |
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| Affiliation: | aDepartment of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China;bSchool of Medicine and Pharmacy, Ocean University of China, Qingdao, China;cSchool of Stomatology, Weifang Medical University, Weifang, China;dShandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of sciences), Jinan, China |
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| Abstract: | Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells. |
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| Keywords: | Histone deacetylase inhibitor anticancer solid tumour drug design |
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