title: Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation.
abstract: Inhibition of lysine-specific demethylase 1 (LSD1) has recently emerged as an attractive therapeutic target for treating cancer and other diseases. As a continuity of our ongoing effort to identify novel small-molecule LSD1-inhibitors, we designed and synthesized a series of resveratrol derivatives, which were shown to be potent inhibitors of LSD1. Among them, compounds 4e and 4m displayed the most potent LSD1-inhibitory activities in enzyme assays, with IC50values of 121 nM and 123 nM, respectively. Biochemistry study and docking analysis indicated that compounds 4e and 4m were reversible LSD1 inhibitors. High content analysis showed that 4e and 4m induced a dose-dependent increase of dimethylated Lys4 of histone H3 and had no impact on the expression of LSD1 in MGC-803 cells. Furthermore, 4e or 4m could remarkably increase the mRNA level of CD86, a surrogate cellular biomarker for LSD1 activity, in MGC-803 cells, suggesting that they are likely to exhibit LSD1-inhibitory activities intracellularly. These findings should encourage further modification of these compounds to produce more potent LSD1 inhibitors with potential anticancer activity.
authors.affiliation: School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China.
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Duan
authors.affiliation: School of Pharmacy, SanQuan College of Xinxiang Medical University, Xinxiang, Henan 453003, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Guan
authors.affiliation: School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhai
authors.affiliation: 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.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Ding
authors.affiliation: School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China.
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Xue-Qi
authors.initials: XQ
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Sun
authors.affiliation: 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. Electronic address: yichaozheng@zzu.edu.cn.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zheng
authors.affiliation: 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. Electronic address: liuhm@zzu.edu.cn.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D000077185:Resveratrol; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013267:Stilbenes; D056466:Histone Demethylases; D000077185:Resveratrol
keywords: Lysine-specific demethylase 1 inhibitors; Resveratrol derivatives; Synthesis