Design, synthesis, and biological evaluation of novel trimethoxyindole derivatives derived from natural products

Piperlongumine, a natural alkaloid, is reported to possess various biological activities. In this study, six analogs with indole moiety have been designed and synthesized using scaffold hopping strategy. They exhibited better antitumor activities than the parent piperlongumine without apparent toxicity in normal cells. Among them, 3-chloro-1-(5,6,7-trimethoxy-1-methyl-1 H -indole-2-carbonyl)-5,6-dihydropyridin-2(1 H )-one showed the best in vitro antitumor activity with the IC 50 value improved in 4–8-fold against four cancer cell lines. In an A549 lung cancer xenograft model, it exhibited a tumor growth inhibition of 54.6%, which is much higher than that of parent piperlongumine (38.3%) and comparable to the positive drug doxorubicin (53.3%). The indole–piperlongumine provides a novel lead compound for anticancer drug discovery. Graphic abstract