SYNTHESIS AND EVALUATION OF ANALOGUES INDOLE-BASED AGENTS AS TUBULIN INHIBITORS USING CELL LINES

*Ayushi Chawla, Shachindra L. Nargund, Ranjan Kumar M.

Combretastatin A-4 (CA-4) is a natural vasodisrupting agent (VDA) derived from the bark of Combretum caffrum and has demonstrated selective activation of tumor vasculature, leading to vessel rupture. It effectively inhibits tubulin polymerization by binding to colchicine sites, inducing mitotic arrest and cytotoxicity at low nanomolar concentrations. Structural activity relationships (SARs) have identified essential modifications, including the 3′-hydroxyl group of the B ring and various substitutions at this position to enhance antitumor activity. CA-4 phosphate (CA-4P), a water-soluble prodrug, has entered clinical trials for its vascular effects in combination with cytotoxic drugs. Inspired by the tubulin-inhibitory properties of vincristine and bromoindirubin, researchers have explored the integration of an indole moiety into CA-4 derivatives to improve efficacy. Given the challenges of drug resistance in microtubule-targeting agents, this study aims to develop novel tubulin inhibitors incorporating the indole ring structure.