Evaluation of a Tubulin-Targeted Pyrimidine Indole Hybrid Molecule as an Anticancer Agent

Several small molecules targeting microtubule dynamics have been developed because microtubules are considered to be one of the most successful cancer chemotherapeutic targets. In this regard, taxol is most worthy to mention which stabilizes microtubule polymer thereby causing defectsinmitotic spindle assembly, chromosome segregation and cell division resulting in cancer inhibition. In this direction, we have earlier reported a small molecule called Pyrimidine-Indole-Hybrid (PIH (P)) which was found to inhibit ciliogenesis by inhibiting both the acetylation and polymerization of tubulin subunits. Here, we have evaluated the anticancer activities of PIH (P) and its water soluble derivatives. Three water soluble derivatives of PIH (P) namely 6 A, 6B and 6 C were synthesized. Among PIH (P) series of compounds, PIH (P) and 6 C were found to be the most potent compounds showing anti-proliferative and cytoskeletal disrupting activities against MCF-7 cells. Not only that, PIH (P) and 6 C also showed a promising effect in preventing cancer cell migration, invasion and colony-formation and helped to reduce spheroid formation by several-folds. They have potential to inhibit the activity of proteins (N-Cadherin, Vimentin) responsible for Epithelial to Mesenchymal Transition (EMT). Hence, this class of compound could be a new antimitotic agent that is different from taxol with respect to mechanism, particularly by destabilizing tubulin rather than causing stabilization.