Design, synthesis and structure–activity relationship studies on erianin analogues as pyruvate carboxylase inhibitors in hepatocellular carcinoma cells

Abstract

A series of novel erianin analogues were designed and synthesized based on the bioisosterism principle by altering the two aromatic rings of erianin, the substituents on the rings and the linker between them. The analogues were evaluated as pyruvate carboxylase (PC) inhibitors in hepatocellular carcinoma cells. It was found that compounds 35 and 36, where fluorine replaces a hydroxyl group, exhibited higher activity than erianin (IC₅₀ value of 17.30 nM) in liver cancer cells with IC₅₀ values of 15.15 nM and 10.05 nM, respectively. Additionally, at a concentration of 10 nM, compounds 35 and 36 inhibited PC with inhibitory rates of 39.10% and 40.15%, respectively, exhibiting nearly identical inhibitory activity to erianin (inhibitory rate of 40.07%). Additionally, a computer simulation docking study demonstrated the basis for better interactions between the receptors and ligands. The fluorine atom of 35 can not only form hydrogen bonds with Lys-1043 (NH⋯F, 2.04 Å), but also form fluorine bonds with the carbonyl groups of Lys-1043 (3.67 Å) and Glu-1046 (3.70 Å), due to the different orientations of the halogens on the B ring warhead. Conversely, the chlorine atom of 34 can only form alkyl hydrophobic interactions with the alkane chain in Lys-1043. Fluorinated compounds 35 and 36 also show better chemical stability and higher log P (clog P = 3.89 for 35 and 36) values than that of erianin (clog P = 3.07), and may be used as candidate compounds for further drug development.