Design, synthesis, and biological evaluation of benzenesulfonyl chloride-substituted evodiamine derivatives as potential PGAM1 inhibitors

Abstract

Evodiamine (EVO) is a quinazoline carboline alkaloid isolated from the fruits of the traditional Chinese herb Evodiae fructus. In the present study, we synthesized thirty EVO derivatives (9–38) with various benzenesulfonyl groups by sulfonylation of the amino group of 3-NH-EVO and thirty benzenesulfonyl chloride substituents. The results of the MTT assay showed that most of the compounds had good antitumor activity on H460, PC9, PC9/GR, H1299 and SW620 cancer cells as well as on normal LO2 cells. Among them, compounds 9, 18 and 28 were more potent than other compounds on H460 cell lines with an IC50 value of 9.1 M, 10.5 M and 9.5 M, respectively, even more potent than the positive PGMI-004A with one IC50 of 31.1 M. The enzymatic activity of representative compounds was further evaluated against phosphoglycerate mutase 1 (PGAM1). The results showed that compound 11 with an IC50 of 0.062 μM and compound 34 with an IC50 of 0.059 μM were similar to the positive drug’s IC50 of 0.052 μM. These results indicated that these compounds could be developed into potential PGAM1 inhibitors. In addition, compounds 9, 18, and 28 could induce apoptosis, block the cell cycle at the G2/M stage, lead to bursting of reactive oxygen species, and induce mitochondrial dysfunction. Overall, the present work showed that the benzenesulfonyl chloride-substituted evodiamine derivatives have good antitumor activity against tumor cells and show promise as anticancer agents.

Keywords

• Benzenesulfonyl chloride
• Evodiamine
• Phosphoglycerate mutase 1 inhibitor
• Structure-activity relationship