Thiophene derivative-loaded nanoparticles mediate anticancer activity through the inhibition of kinases and microtubule assembly.

ABSTRACT

Different tetrahydrobenzo[b]thiophene derivatives were explored as new tubulin polymerization destabilizers to arrest tumor cell mitosis. A series of compounds incorporating the tetrahydrobenzo[b]thiophene scaffold were synthesized, and their biological activities were investigated. The cytotoxicity of each of the synthesized compounds was assessed against a range of cell lines. Specifically, the benzyl urea tetrahydrobenzo[b]thiophene derivative, 1-benzyl-3-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)urea (BU17), was identified as the most potent compound with broad-spectrum antitumor activity against several cancer cell lines. The potential mechanism(s) of action were investigated where dose-dependent G2/M accumulation and A549 cell cycle arrest were detected. Additionally, A549 cells treated with BU17 expressed enhanced levels of caspase 3 and 9, indicating the induction of apoptosis. Furthermore, it was found that BU17 inhibits WEE1 kinase and targets tubulin by blocking its polymerization. BU17 was also formulated into PLGA nanoparticles, and it was demonstrated that BU17-loaded nanoparticles could significantly enhance antitumor activity compared to the soluble counterpart.