Synthesis, biological activities, and docking studies of d-pantolactone derivatives as novel FAS inhibitors

Hua Fang; Jianlin He; Tan Ran; Hui Chen; Wenhui Jin; Bowen Tang; Zhuan Hong; Meijuan Fang

doi:10.1016/j.bmc.2019.115069

Synthesis, biological activities, and docking studies of d-pantolactone derivatives as novel FAS inhibitors

Bioorg Med Chem. 2019 Oct 15;27(20):115069. doi: 10.1016/j.bmc.2019.115069. Epub 2019 Aug 24.

Authors

Hua Fang¹, Jianlin He², Tan Ran², Hui Chen³, Wenhui Jin³, Bowen Tang⁴, Zhuan Hong⁵, Meijuan Fang⁶

Affiliations

¹ Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China; Xiamen Ocean Vocational College, Xiamen 361005, China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen 361005, China. Electronic address: hfang@tio.org.cn.
² Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen 361005, China.
³ Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China; Xiamen Ocean Vocational College, Xiamen 361005, China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen 361005, China.
⁴ School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
⁵ Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China; Xiamen Ocean Vocational College, Xiamen 361005, China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen 361005, China. Electronic address: zhong@tio.org.cn.
⁶ School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China. Electronic address: fangmj@xmu.edu.cn.

PMID: 31492533
DOI: 10.1016/j.bmc.2019.115069

Abstract

A novel series of fatty acid synthase (FAS) inhibitors with D-(-)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC₅₀ values in the range of 13.68 ± 1.52-33.19 ± 1.39 μM, reference inhibitor C75 has IC₅₀ value of 13.86 ± 2.79 μM. Eight compounds (3c, 3d, 3e, 3f, 3j, 3m, 3q and 3r) also displayed inhibitory effect on lipid accumulation in human HepG2 cells. Additionally, the molecular docking study revealed that compound 3m having good inhibition activity against FAS and lipid accumulation also showed promising binding affinities with hFAS, while its binding model with hFAS (PDB ID: 4PIV) was different from that of reference compound C75.

Keywords: Fatty acid synthase (FAS); Lipid accumulation; Molecular docking; d-pantolactone derivatives.

Publication types

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

MeSH terms

4-Butyrolactone / analogs & derivatives*
4-Butyrolactone / chemical synthesis
4-Butyrolactone / chemistry
4-Butyrolactone / pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Hep G2 Cells
Humans
Lipids / antagonists & inhibitors
Molecular Docking Simulation*
Molecular Structure
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
fas Receptor / antagonists & inhibitors*
fas Receptor / metabolism

Substances

Enzyme Inhibitors
FAS protein, human
Lipids
fas Receptor
pantolactone
4-Butyrolactone