Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Autor: Wang DD; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China. Electronic address: wangdandan801@126.com., Wang ZZ; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China., Liu WC; Asymchem Biotechnology (Tianjin) Co., Ltd, Tianjin 300457, China., Qian XK; Translational Medicine Research Center, Guizhou Medical University, University Town, Guian New District, Guizhou 550025, China. Electronic address: qxkgood@hotmail.com., Zhu YD; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang 550025, China., Wang TG; Tangshan Boshide Medical Devices Co., Ltd, Tangshan 063599, China., Pan SM; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China., Zou LW; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: chemzlw@163.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107536. Date of Electronic Publication: 2024 Jun 05.
DOI: 10.1016/j.bioorg.2024.107536
Abstrakt: Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.
Competing Interests: 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.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: