Identification of selenium-containing benzamides as potent microtubule-targeting antitumor agents.

IMB5046, a microtubule inhibitor discovered by our team, served as the lead compound for designing a series of selenium-containing benzoates and benzamides. Among these, compound 2g emerged as a lead candidate, demonstrating potent antiproliferative activity. Mechanistic studies revealed that 2g bound to the colchicine site of tubulin, caused G2/M cell cycle arrest, and generated ROS. Notably, 2g exhibited exceptional efficacy in P-gp overexpressing MCF7/ADR and KB cell lines, with drug-resistance indices (DRI) of 0.83 and 0.58, respectively, significantly outperforming colchicine (DRIs: 25.4 and 8.03) and paclitaxel (DRIs: 41.0 and 4.96). In an MCF-7 xenograft model, 2g (25 mg/kg, IP) achieved a tumor growth inhibition rate of 57.2 %, surpassing IMB5046 (47.6 %). To enhance solubility and pharmacokinetics, prodrug 2g-P was developed, showing 69 % bioavailability but reduced in vivo efficacy. Further investigation is warranted to elucidate the factors underlying the discrepancy, such as the efficiency of prodrug-to-drug conversion and intracellular accumulation of active 2g. In summary, our study not only identified a novel selenium-containing lead compound, but also provided important insights into prodrug design. These findings lay a solid foundation for the development of next-generation microtubule-targeting agents capable of overcoming drug resistance.