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Design,synthesis and biological activity of 3-oxoamino-benzenesulfonamides as selective and reversible LSD1 inhibitors
Institution:1. Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Laboratory of Epigenetics, Institute of Biochemical Sciences, Fudan University, 131 Dong’An Road, Shanghai 200032, PR China;3. Department of Biochemical Engineering, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;4. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;5. Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, PR China;1. Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy;2. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;3. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Roma, Italy;1. School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China;2. School of Pharmacy, SanQuan College of Xinxiang Medical University, Xinxiang, Henan 453003, China;3. Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China;1. Department of Pharmaceutical Engineering, Department of Biomedical Engineering, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China;2. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Epigenetics and Metabolism, Ministry of Science and Technology, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China;3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China;4. Shanghai ChemPartner Co. Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
Abstract:Lysine specific demethylase 1 (LSD1) is a flavin-dependent amine oxidase that selectively removes one or two methyl groups from H3 at Lys4 and is recognized as a promising therapeutic target for cancer and other diseases. Here, a series of 3-oxoamino-benzenesulfonamides were synthesized and evaluated for their inhibitory activity against LSD1. Compounds 7b and 7h showed the most potent inhibition with the IC50 values of 9.5 and 6.9 μM, respectively. Furthermore, the LSD1 inhibition of 7b and 7h were reversible and selective. Docking study presented the possible binding mode between 7b, 7h and the LSD1 active site. Taken together, 3-oxoamino-benzenesulfonamides may represent a new class of reversible LSD1 inhibitors and 7b and 7h were two hit compounds deserved further structural optimization.
Keywords:LSD1  Inhibitors  Selective  Reversible  Docking  DCM"}  {"#name":"keyword"  "$":{"id":"k0035"}  "$$":[{"#name":"text"  "_":"dichloromethane  TBSCl"}  {"#name":"keyword"  "$":{"id":"k0045"}  "$$":[{"#name":"text"  "$$":[{"#name":"italic"  "_":"tert"}  {"#name":"__text__"  "_":"-butyldimethylsilyl chloride  TBAF"}  {"#name":"keyword"  "$":{"id":"k0055"}  "$$":[{"#name":"text"  "_":"tetrabutylammonium fluoride  rt"}  {"#name":"keyword"  "$":{"id":"k0065"}  "$$":[{"#name":"text"  "_":"room temperature  DMF"}  {"#name":"keyword"  "$":{"id":"k0075"}  "$$":[{"#name":"text"  "_":"N  N-dimethylformamide  THF"}  {"#name":"keyword"  "$":{"id":"k0085"}  "$$":[{"#name":"text"  "_":"tetrahydrofuran  DIEA"}  {"#name":"keyword"  "$":{"id":"k0095"}  "$$":[{"#name":"text"  "_":"N  N-diisopropylethylamine
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