Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells
Yu-Chen Liu,
Gang Wei,
Zhi-Qiang Liao,
Fang-Xin Wang,
Chunxiao Zong,
Jiannan Qiu,
Yifei Le,
Zhi-Ling Yu,
Seo Young Yang,
Heng-Shan Wang,
Xiao-Bing Dou,
Cai-Yi Wang
Affiliations
Yu-Chen Liu
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Gang Wei
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin 541004, China
Zhi-Qiang Liao
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin 541004, China
Fang-Xin Wang
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin 541004, China
Chunxiao Zong
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Jiannan Qiu
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Yifei Le
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Zhi-Ling Yu
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
Seo Young Yang
Department of Biology Education, Teachers College and Institute for Phylogenomics and Evolution, Kyungpook National University, Daegu 41566, Republic of Korea
Heng-Shan Wang
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Normal University, Guilin 541004, China
Xiao-Bing Dou
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Cai-Yi Wang
College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 μM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.
