Disrupting microtubule dynamics to rewire apoptosis, differentiation, and EMT programs in oral squamous cell carcinoma through indenamine derivatives.

Oral squamous cell carcinoma (OSCC) remains a major global health burden with limited treatment options and high rates of recurrence. In this study, we screened 22 synthesized indenamine derivatives designed to target microtubules and identified three lead compounds-SSB2, SSB21, and SSB22 showing potent cytotoxicity against OSCC cells while sparing normal epithelial cells. These compounds induced G2/M cell cycle arrest, disrupted microtubule organization, and triggered apoptotic cell death. Transcriptomic analysis revealed significant downregulation of oncogenic and cell cycle-related genes and upregulation of tumor suppressors and differentiation markers, suggesting a shift toward terminal differentiation. The compounds also modulated genes involved in epithelial-to-mesenchymal transition (EMT), indicating potential to limit metastasis. Collectively, our cellular and molecular analyses demonstrate that these indenamine derivatives exert potent, selective anticancer activity in OSCC through microtubule destabilization and reprogramming of key cellular pathways. Molecular docking studies of lead indenamines showed similar binding and affinities at colchicine binding site of α,β-tubulin. These findings highlight the potential of these indenamine derivatives in OSCC therapeutics.