Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

doi:10.1016/j.ejmech.2022.114866

. 2022 Dec 15:244:114866.

doi: 10.1016/j.ejmech.2022.114866. Epub 2022 Oct 28.

Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

Yingle Mao¹, Jiaomeng Li², Chunping Tang³, Biao Ma⁴, Zhijian Xu⁵, Changqiang Ke³, Lu Feng³, Haiyan Zhang⁶, Sheng Yao⁷, Hui-Xiong Dai⁸, Yang Ye⁹

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, People's Republic of China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁴ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁵ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁶ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. Electronic address: yaosheng@simm.ac.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. Electronic address: hxdai@simm.ac.cn.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, People's Republic of China. Electronic address: yye@simm.ac.cn.

PMID: 36368255
DOI: 10.1016/j.ejmech.2022.114866

Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

Yingle Mao et al. Eur J Med Chem. 2022.

. 2022 Dec 15:244:114866.

doi: 10.1016/j.ejmech.2022.114866. Epub 2022 Oct 28.

Authors

Yingle Mao¹, Jiaomeng Li², Chunping Tang³, Biao Ma⁴, Zhijian Xu⁵, Changqiang Ke³, Lu Feng³, Haiyan Zhang⁶, Sheng Yao⁷, Hui-Xiong Dai⁸, Yang Ye⁹

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, People's Republic of China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁴ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁵ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
⁶ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. Electronic address: yaosheng@simm.ac.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. Electronic address: hxdai@simm.ac.cn.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, People's Republic of China. Electronic address: yye@simm.ac.cn.

PMID: 36368255
DOI: 10.1016/j.ejmech.2022.114866

Abstract

Lipids-lowering is considered as the most effective approach to decrease the risk of Atherosclerotic cardiovascular disease (ASCVD), of which atherosclerosis is the most common cause. Natural products containing a unique type of α-pyrone was reported to suppress atherosclerosis in which α-pyrone might be considered as an important pharmacore. In this study, an efficient one-pot intramolecular C-H activation strategy was applied to the synthesis of potentially bioactive α-pyrone derivatives. As the result, three different scaffolds were quickly and conveniently generated, including thiophenes, pyrrole and indole derivatives. Among of them, eight α-pyrone derivatives showed potential effects to promote the uptake of LDL in HepG2 cells. Active unique α-pyrones compounds exhibiting potent in vitro and in vivo lipids-lowering effects, and a novel mechanism associated with the regulation of LXR-IDOL-LDLR axis, the new pathway targeted pharmacologically to control plasma cholesterol levels, were disclosed firstly in this study.

Keywords: C–H activation; In vivo lipids-lowering effect; LDL uptaking; LXR-IDOL-LDLR axis; One-pot intramolecular cyclization; α-Pyrone derivatives.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

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Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

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