Design, Synthesis and Anticancer Activity of 6-Substituted-1-(3,4,5-trimethoxyphenyl)-1H-indole Against Tubulin Polymerisation

Using virtual FragLites screening and a fragment-based drug discovery (FBDD) strategy, we designed and synthesized a series of 6-substituted-1-(3,4,5-trimethoxyphe-nyl)-<i>1H</i>-indole derivatives as potential tubulin polymerization inhibitors. Among them, compound <b>3g</b> exhibited the best antiproliferative activity within this series and affected microtubule dynamics in a concentration-dependent manner. Further studies indicated that <b>3g</b> induced G₂/M cell-cycle arrest and triggered apoptosis in MCF-7 cells. In vivo, <b>3g</b> achieved tumor growth inhibition rates of 23.3% and 44.2% at 20 mg/kg and 50 mg/kg, respectively, without evident systemic toxicity. These results suggest that <b>3g</b> shows preliminary antitumor efficacy and may serve as a starting point for further mechanistic and structural studies. Further optimization and detailed pharmacokinetic and toxicity studies are merited to advance these inhibitors in preclinical development.