A novel ring-opened ebselen scaffold with potent anti-angiogenic activity against cancer: synthesis, biological evaluation, and molecular docking.

Optimizing ring-opened scaffolds from the benzisoselenazolone (BISZ) core offers a promising strategy for developing novel anticancer agents. Herein, eleven new ebselen analogues (3a-k) featuring a symmetric bis-open-ring scaffold were synthesized and evaluated for in vitro antiproliferative activity against seven human cancer cell lines. Results shown compound 3d was the most potent across all seven tested panels, including lung carcinoma A549 (IC50 = 3.75 μM), esophageal KYSE-30 (1.55 μM), hepatocellular HCCLM3 (5.57 μM), prostate PC3 (2.77 μM), colorectal HCT116 (14.12 μM), hepatocellular HepG2 (14.33 μM), and breast MDA-MB-231 (8.28 μM). At 6.25 μM, 3d significantly inhibited angiogenesis in transgenic zebrafish, reducing subintestinal vessel area by 25.6% (p < 0.001) and intersegmental vessel number by 15.8% (p < 0.01), suggesting a potential anti-angiogenic activity against cancer. Docking and MD simulations suggested a possible interaction of 3d to MetAP2.