Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors

Qiangqiang Wei; Liankuo Mei; Yifei Yang; Hui Ma; Hongyi Chen; Huibin Zhang; Jinpei Zhou

doi:10.1016/j.bmc.2018.03.014

Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors

Bioorg Med Chem. 2018 Aug 7;26(14):3866-3874. doi: 10.1016/j.bmc.2018.03.014. Epub 2018 Mar 9.

Authors

Qiangqiang Wei¹, Liankuo Mei², Yifei Yang¹, Hui Ma², Hongyi Chen¹, 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@cpu.edu.cn.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

PMID: 30049586
DOI: 10.1016/j.bmc.2018.03.014

Abstract

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC₅₀ = 0.527 μM, ACC2 IC₅₀ = 0.397 μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC₅₀ values of 1.92 μM, 0.38 μM, 1.22 μM, 2.05 μM and 5.42 μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.

Publication types

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

MeSH terms

Acetyl-CoA Carboxylase / antagonists & inhibitors*
Acetyl-CoA Carboxylase / metabolism
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Amides
Antineoplastic Agents
Enzyme Inhibitors
Spiro Compounds
Acetyl-CoA Carboxylase