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Design, synthesis and biological activity of N-(3-substituted-phenyl)benzenesulfonamides as selective and reversible LSD1 inhibitors

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Abstract

Lysine specific demethylase 1 plays a crucial role in regulating histone methylation at residues K4 and K9 on histone H3 and over-expresses in a variety of cancers. Here we designed, synthesized and evaluated a series of N-(3-substituted-phenyl)benzenesulfonamides as reversible lysine specific demethylase 1 inhibitors. All the compounds exhibited lysine specific demethylase 1 inhibition with the half maximal inhibitory concentration (IC50) values between 7.5 and 68 μM. Three most active compounds 2a, 2c and 2i displayed only modest effect on flavin adenine dinucleotide-dependent enzymes mono-amine oxidases A and B, and their reversibilities of lysine specific demethylase 1 inhibition were confirmed. Molecular docking was also carried out to predict the binding mode of 2a into the active site of lysine specific demethylase 1. Taken together, N-(3-substituted-phenyl)benzenesulfonamides including 2a represent a new class of selective and reversible lysine specific demethylase 1 inhibitors with pharmaceutical research.

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Fig. 1
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Abbreviations

TEA:

Triethylamine

DIPEA:

N,N-Diisopropylethylamine

EDCI:

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

HOBt:

N-Hydroxybenzotriazole

rt:

Room temperature

PyBOP:

Benzotriazol-1-yl-oxytripyrrolidinophosphonium

DMAP:

4-Dimethylaminopyridine

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Acknowledgments

X. Z. thanks the financial support by the Natural Science Foundation of Jiangsu Province (BK20161458), the Fundamental Research Funds for the Central Universities (JKPZ2013001), the Graduate Innovative Foundation supported by Huahai Pharmaceuticals Co., Ltd. (CX14S-004HH) and the Open Project Program of Jiangsu Key Laboratory of Drug Screening (JKLDS2015KF-03). F. L. thanks the financial support by China “Thousand Youth Talents” (KHH1340001) and NSFC grant (91419306).

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Nanjing, People’s Republic of China

      Xiaoming Zha, Liming Wu, Fangxia Zou, Jiayue Xi & Tianfang Ma

    2. Department of Biochemical Engineering, Nanjing, People’s Republic of China

      Xiaoming Zha, Liming Wu, Fangxia Zou, Jiayue Xi, Tianfang Ma, Dawei Deng & Yueqing Gu

    3. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People’s Republic of China

      Liming Wu & Jinpei Zhou

    4. Laboratory of Epigenetics, Institute of Biochemical Sciences, Fudan University, 131 Dong’An Road, Shanghai, 200032, People’s Republic of China

      Siyuan Xu & Fei Lan

    5. Shanghai ChemPartner Co. Ltd., Zhangjiang Hi-Tech Park, Shanghai, 201203, People’s Republic of China

      Rongfeng Liu & Yu-Chih Liu

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    1. Xiaoming Zha
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    2. Liming Wu
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    Correspondence to Xiaoming Zha, Jinpei Zhou or Fei Lan.

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    Conflict of interest

    F. L. is a shareholder of Constellation Pharmaceuticals Inc. as well as a consultant of Active Motif. The remaining authors declare that they have no conflict of interests.

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    Xiaoming Zha, Liming Wu and Siyuan Xu contributed equally to this article.

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    Zha, X., Wu, L., Xu, S. et al. Design, synthesis and biological activity of N-(3-substituted-phenyl)benzenesulfonamides as selective and reversible LSD1 inhibitors. Med Chem Res 25, 2822–2831 (2016). https://doi.org/10.1007/s00044-016-1706-8

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