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 -IC50 values falling below 20 mu M. 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 mu M. 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.

Automated summary

A series of novel covalent S-acylation inhibitors were designed through synthesis, and most of them exhibited better anti-proliferation effects on MCF-7, MGC-803, and U937 cell lines compared to 2-BP. Compound 8d, 8i, 8j, and 10e showed significant inhibitory effects on MCF-7 cells, with -IC50 values below 20 μM. Furthermore, these inhibitors had less toxic effects on 3T3 cell line than 2-BP. Inhibition of S-acylation was observed for most of the compounds, with 8i showing the highest inhibitory rate of 89.3% at a concentration of 20 μM. Molecular docking revealed the conjugation of 8i with surrounding amino acids. Additionally, 8i not only suppressed the migration of MCF-7 cells but also induced cell apoptosis by arresting them in the G0/G1 phase.