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

Ring-opened scaffolds from the benzisoselenazolone (BISZ) core offers a promising strategy for developing novel selenium-containing anticancer agents. • Novel 11 symmetric bis-open-ring ebselen analogues were synthesized, and 3d exhibited antiproliferative activity against seven human cancer cell lines, with IC₅₀ values ranging from 1.55 to 14.33 μM. Compound 3d also inhibited angiogenesis in transgenic zebrafish, reducing subintestinal vessel area by 25.6% and intersegmental vessel number by 15.8%. • Virtual screening and 100 ns molecular dynamics simulations revealed stable binding of 3d to human methionine aminopeptidase 2 (MetAP2), with a MM-GBSA binding free energy of −22.14 kcal/mol. • The dual inhibitory effects on cancer cell proliferation and angiogenesis suggest a promising mechanism for new ebselen open-ring analogue 3d as an anticancer agent. 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 (IC 50  = 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. A novel ring-opened ebselen scaffold with potent anti-angiogenic activity against cancer: synthesis, biological evaluation, and molecular docking. Download: Download high-res image (118KB) Download: Download full-size image