Silicon-tethered colchicine aryne cyclo-adduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases

The anticancer potential of colchicine and its derivatives has garnered significant attention due to their ability to bind with tubulin, a critical cytoskeletal protein crucial for cell division's mitotic phase. In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small focussed library of derivatives. We assessed their anticancer activity against various cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, the silicon-tethered compound B-4a demonstrated the highest potency against breast cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (cdk-2 and cdk-4) and their associated cyclins (cyclin B1, cyclin D1), inducing apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, distinct from the parent colchicine, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects were attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including Vimentin and Twist-1, as well as the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.