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

The d -pantolactone derivative, (R)-4-methoxy-benzoic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (3m), exhibited fatty acid synthase inhibitory activity with IC 50 value of 13.68 ± 2.79 μM. Like reference compound C75 , compound 3m also showed similar inhibition of lipid accumulation on the proliferation of HepG2 cells. Molecular docking was further used to predict the interaction model of 3m and KR domain of human fatty acid synthase. 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 IC 50 values in the range of 13.68 ± 1.52–33.19 ± 1.39 μM, reference inhibitor C75 has IC 50 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. [ABSTRACT FROM AUTHOR]