Tubulin Inhibitors(Indian Institute of Technology Indore)

As the structural foundation of microtubules, tubulin represents a pivotal molecular target in anticancer drug discovery. The design and evaluation of small-molecule tubulin polymerization inhibitors continues to be a productive strategy for identifying next-generation chemotherapeutic agents. Based on systematic structural analysis of known tubulin inhibitors targeting the colchicine-binding site and available computational tubulin-ligand models, a focused library of 3-aryl-5-(3,4,5-trimethoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine derivatives was rationally designed and synthesized as candidate tubulin polymerization inhibitors. Among these, compound 10u demonstrated the most pronounced antiproliferative activity, with IC₅₀ values spanning 0.085-0.13 μM across three human cancer cell lines (Huh7, HeLa, and A549). Mechanistic studies indicated that 10u potently suppresses tubulin polymerization, dismantles the intracellular microtubule network, arrests the cell cycle at the G₂/M phase, and subsequently induces apoptotic cell death. In an orthotopic Huh7 mouse model, 10u significantly inhibited tumor growth without eliciting observable systemic toxicity. Collectively, these results highlight 10u as a promising tubulin polymerization inhibitor with potent dual-phase anticancer activity, supporting its further development as a potential therapeutic agent.

Tubulin inhibitors, such as taxanes and vinca alkaloids, target the microtubule and are limited by multidrug resistance, toxicity, and myelosuppression. Phenylahistin derivatives, a natural marine product, exert an anticancer effect by depolymerizing microtubules and disrupting vasculature and treat chemotherapy-induced neutropenia by activating GEF-H1, which binds to the colchicine site. To discover new phenylahistin derivatives, 24 novel furan-type phenylahistin derivatives were designed and synthesized by replacing the 1,3-imidazol-4-yl group with furan-type substitutions. Antitumor proliferation screening showed that 10u (16 nM) and 10v (21 nM) were more effective than plinabulin (26 nM). Compounds 10u and 10v induced cell death through the mitochondrial pathway. Compounds 10u and 10v also induced cancer cell apoptosis by inhibiting Bcl-2, upregulating P53, reducing mitochondrial membrane potential, and elevating ROS levels, disrupting microtubule networks, inducing G2/M arrest, and promoting apoptosis via caspase-3 activation. And molecular docking revealed that the furan-based derivatives formed important bonds with β-tubulin.