Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR

Microtubule target agents (MTAs) are widely-used clinical anti-cancer drugs for decades, but the acquired drug resistance severely restricted their application. Thioredoxin reductases (TrxR) was reported to be overexpressed in most tumors and closely related to high risk of cancer recurrence and drug resistance, making it a potential target for anticancer drug discovery. Multi-target-directed ligands (MTDLs) by a single molecule provide a logical and alternative approach to drug combinations. In this work, based on the structure-activity relationships obtained in our previous study, some structure modifications were performed. On one hand, the retained skeleton structure of MTAs endowed its tubulin polymerization inhibition activity, on the other hand, the selenium-containing structure and alpha,beta-unsaturated ketone moiety endowed the TrxR inhibition activity. As results, the newly obtained compounds exhibited superior anti-proliferative activities towards various human cancer cells and drugresistance cells, and displayed high selectivity towards various human normal cells. The mechanism study revealed that the dual effect of cell cycle arrest triggered by targeting tubulin and the abnormal accumulation of ROS caused by TrxR inhibition eventually lead to cell apoptosis. Notably, compared with the MTA agents CA-4P, and the TrxR inhibitor Ethaselen, the optimized compound 14c, which served as dual-targeting inhibitor of tubulin and TrxR, exerted greatly improved in vivo anti-tumor activity. In summary, 14c deserved further consideration for cancer therapy. (C) 2021 Published by Elsevier Masson SAS.

Automated summary

The study obtained compounds with superior anti-proliferative activities through structure modification, showing high selectivity in various human cancer cells and drug-resistant cells. Mechanism study revealed these compounds induced cell apoptosis through a dual mechanism of targeting tubulin and TrxR.