Design, Synthesis, and Selective Antiproliferative Activity of Indolizine Derivatives as Microtubule Destabilizers

The development of selective anticancer agents with minimal off-target toxicity remains a major therapeutic goal. In this study, we synthesized and evaluated a series of 32 indolizine derivatives for antiproliferative activity against oral (CAL-27), breast (BT-20), and gastric (HGC-27) cancer cell lines, as well as non-tumoral fibroblasts (OHMF). Compounds 8e and 8h emerged as potent and selective candidates, exhibiting nanomolar IC₅₀ values (47-117 nM) and negligible cytotoxicity toward healthy cells. These compounds induced G2/M cell-cycle arrest, inhibited tubulin polymerization, and modulated proteins related to apoptosis and proliferation, including p-AKT, cyclin D1, Bcl-2, and p21. Docking studies confirmed their interaction with the colchicine-binding site of tubulin. Together, the results support further investigation of these compounds as microtubule-interacting agents with selective antiproliferative activity.