Diversity-oriented synthesis of marine polybrominated diphenyl ethers as potential KCNQ potassium channel activators

Lai-Xin Liu; Ru-Rong Gu; Yang Jin; Xue-Qin Chen; Xu-Wen Li; Yue-Ming Zheng; Zhao-Bing Gao; Yue-Wei Guo

doi:10.1016/j.bioorg.2022.105909

Diversity-oriented synthesis of marine polybrominated diphenyl ethers as potential KCNQ potassium channel activators

Bioorg Chem. 2022 Sep:126:105909. doi: 10.1016/j.bioorg.2022.105909. Epub 2022 May 27.

Authors

Lai-Xin Liu¹, Ru-Rong Gu², Yang Jin¹, Xue-Qin Chen³, Xu-Wen Li⁴, Yue-Ming Zheng⁵, Zhao-Bing Gao⁶, Yue-Wei Guo⁷

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
⁵ Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
⁶ Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: [email protected].
⁷ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: [email protected].

PMID: 35661526
DOI: 10.1016/j.bioorg.2022.105909

Abstract

Natural polybrominated diphenyl ethers, often isolated from marine sponges, have been reported to possess various biological activities, such as antibacterial, antioxidant and antidiabetic effects. Via a high throughput screening of our marine natural product library, the polybrominated diphenyl ether 3 was found to display a KCNQ potassium channel activation effect. To obtain more compound 3 related natural products and their derivatives for further bioactivity study, a diversity-oriented synthesis was conducted, leading to the successful synthesis of five polybrominated diphenyl ether natural products (1-4, 6) and 30 new derivatives. Compound 3 was found to preferentially potentiate KCNQ1 potassium channel, whereas 17h relatively activated KCNQ2 potassium channel. The structure-activity relationship was analyzed assisted by molecular docking and 17h was further conducted for its agonistic mechanism study on KCNQ2 channel. This research work may give an insight for the discovery of marine polybrominated diphenyl ether derived new drug leads.

Keywords: KCNQ potassium channel; Marine Natural product; Polybrominated diphenyl ethers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Products* / pharmacology
Halogenated Diphenyl Ethers / pharmacology
KCNQ Potassium Channels
Molecular Docking Simulation
Porifera*

Substances

Biological Products
Halogenated Diphenyl Ethers
KCNQ Potassium Channels