Design, synthesis, and biological evaluation of novel 3-aryl-4-(3,4,5-trimethoxyphenyl)selenophene derivatives as new tubulin inhibitors

Microtubules, composed of tubulin subunits, represent a critical target in anticancer drug discovery. The design and evaluation of small-molecule inhibitors targeting tubulin polymerisation continue to hold significant promise for advancing cancer therapeutics. Based on structural insights into tubulin polymerisation inhibitors and tubulin interaction models, a novel series of 3-aryl-4-(3,4,5-trimethoxyphenyl)selenophene derivatives were designed as potential tubulin polymerisation inhibitors. Among the synthesised analogs, compound 7i, featuring a selenophene linker, demonstrated superior antiproliferative activity against Huh7, MCF-7, and SGC-7901 cancer cell lines, with IC₅₀ values slightly lower than those of combretastatin A-4 (CA-4). Structure-activity relationship studies revealed that electron-donating substituents at the para-position of the B-ring significantly enhanced cytotoxic potency. Mechanistic studies revealed that compound 7i effectively inhibited tubulin polymerisation, disrupted microtubule networks, induced G2/M cell cycle arrest, and triggered apoptosis in cancer cells. These results underscore the potential of incorporating selenophene into the CA-4 scaffold as a promising strategy for developing potent tubulin polymerisation inhibitors, offering new avenues for cancer therapy.