Design, synthesis and biological activity evaluation of novel covalent S -acylation inhibitors

In order to obtain diverse S -acylation inhibitors and address the defects of existing S- acylation inhibitors, a series of novel covalent S -acylation inhibitors are designed through synthesis. According to the results of MTT assay, most compounds produce a better anti-proliferation effect on MCF-7, MGC-803 and U937 cell lines than 2-BP. Among them, 8d , 8i , 8j and 10e exert a significant inhibitory effect on MCF-7 cell, with the IC 50 values falling below 20 μM. Besides, the toxic effects of some compounds on 3T3 cell line are less significant than 2-BP . According to the results of acyl-biotin exchange (ABE) experiment, most of them could inhibit S -acylation, and 8i performs best in this respect, with the inhibitory rate reaching 89.3% at the concentration of 20 μM. The results of molecular docking show the conjugation of 8i with surrounding amino acids. Additionally, 8i could not only suppress the migration of MCF-7 cell line, but also cause it to stagnate in G0/G1 phase, thus promoting cell apoptosis. Graphical abstract