Discovery of novel 9H-purin derivatives as dual inhibitors of HDAC1 and CDK2 |
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| Institution: | 1. Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China;2. Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China;1. Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China;2. National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China;3. Health Science Center, Shenzhen University, Shenzhen 518060, PR China;4. College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, PR China;5. Department of Pharmacy, Faculty of Science, National University of Singapore, 117543, Singapore;6. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China;1. Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;2. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;4. Shanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, China |
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| 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 and potential dual HDAC/CDK inhibitors. |
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| Keywords: | HDACs CDKs Dual inhibitors Purin Antitumor |
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