Design, synthesis and biological evaluation of novel chroman derivatives as non-selective acetyl-CoA carboxylase inhibitors

Qiangqiang Wei; Liankuo Mei; Pan Chen; Xinrui Yuan; Huibin Zhang; Jinpei Zhou

doi:10.1016/j.bioorg.2020.103943

Design, synthesis and biological evaluation of novel chroman derivatives as non-selective acetyl-CoA carboxylase inhibitors

Bioorg Chem. 2020 Aug:101:103943. doi: 10.1016/j.bioorg.2020.103943. Epub 2020 May 15.

Authors

Qiangqiang Wei¹, Liankuo Mei², Pan Chen¹, Xinrui Yuan², Huibin Zhang³, Jinpei Zhou⁴

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

PMID: 32554277
DOI: 10.1016/j.bioorg.2020.103943

Abstract

Acetyl-CoA carboxylases (ACCs) are the rate-limiting enzymes in the de no lipogenesis, which play an important role in the synthesis and oxidation of fatty acid. Recent research reveals that ACCs are tightly relevant to many kinds of metabolic diseases and cancers. In this study, we synthesized a series of chroman derivatives and evaluated their ACCs inhibitory activities, obtaining compound 4s with IC₅₀ value of 98.06 nM and 29.43 nM of binding activities in ACC1 and ACC2, respectively. Compound 4s exhibited the most potent anti-proliferation activity against A549, H1975, HCT116 and H7901 cell lines (values of IC₅₀: 0.578 μΜ, 1.005 μΜ, 0.680 μΜ and 1.406 μΜ, respectively). Docking studies were performed to explain the structure-activity relationships. These results indicate that compound 4s is a promising ACC1/2 inhibitor for the potent treatment of cancer.

Keywords: Acetyl-CoA inhibitors; Anticancer; Molecular docking.

Publication types

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

MeSH terms

Acetyl-CoA Carboxylase / antagonists & inhibitors*
Cell Line, Tumor
Chromans / chemical synthesis
Chromans / chemistry*
Chromans / pharmacology*
Drug Design*
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Structure-Activity Relationship

Substances

Chromans
Enzyme Inhibitors
Acetyl-CoA Carboxylase