Thiophene Derivative-Loaded Nanoparticles Mediate Anticancer Activity Through the Inhibition of Kinases and Microtubule Assembly

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

Automated summary

Different tetrahydrobenzo[b]thiophene derivatives, especially the benzyl urea derivative BU17, have been identified as potent antitumor compounds with broad-spectrum activity against several cancer cell lines through inhibiting tubulin polymerization. BU17 induces apoptosis, potentially by targeting WEE1 kinase and tubulin. Furthermore, BU17-loaded PLGA nanoparticles exhibit significantly enhanced antitumor activity compared to the soluble form.