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  3. Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation

Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation

  • Eur J Med Chem. 2017 Jan 27;126:246-258. doi: 10.1016/j.ejmech.2016.11.035.
Ying-Chao Duan 1,  Yuan-Yuan Guan 2,  Xiao-Yu Zhai 1,  Li-Na Ding 3,  Wen-Ping Qin 1,  Dan-Dan Shen 3,  Xue-Qi Liu 3,  Xu-Dong Sun 3,  Yi-Chao Zheng 4,  Hong-Min Liu 5
Affiliations

Affiliations

  • 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.
  • 4 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: [email protected].
  • 5 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: [email protected].
PMID: 27888721 DOI: 10.1016/j.ejmech.2016.11.035
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 IC50 values 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.

Keywords

Lysine-specific demethylase 1 inhibitors; Resveratrol derivatives; Synthesis.

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