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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-1H-indole-2-carbonyl)-5,6-dihydropyridin-2(1H)-one showed the best in vitro antitumor activity with the IC50 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.

(20S,21S)-7-Cyclohexyl-21-fluorocamptothecin was discovered by a fluorine drug design strategy with potent antitumor activity and increased metabolic stability. In continuous efforts to find novel antitumor agents derived from natural product camptothecin, 20-carbamates of the active compound (20S,21S)-7-cyclohexyl-21-fluorocamptothecin have been designed and synthesized. Among them, one compound with the diethylamino group showed greater antiproliferative activity than the other 20-carbamate derivatives. The following biological activity assays indicated that the above compound is a valuable lead compound with excellent Topo I inhibitory activity and solution stability.

The ATP-adenosine pathway has been recently identified as an attractive immune-oncology target and several drug candidates have been entered clinic trials. Inspired by the report of the first small-molecule CD73inhibitor AB680, we describe the discovery of natural product ellagic acid as a dual CD73 and CD39 inhibitor with an IC50 value of 1.85 ± 0.21 μM and 0.50 ± 0.22 μM, respectively. The result of cytotoxicity assays indicated that ellagic acid is a valuable lead compound with low cytotoxicity effect for immune therapy.

Active natural productscan be valuable lead compounds and numerous drugs derived from natural products have successfully entered the clinic. Arenobufagin, one of the important active components of toad venom, indicates significant antitumor activities with limited preclinical development for its strong cardiotoxicity. Ten 3-monopeptide substituted arenobufagin derivatives have been designed and synthesized. Antitumor activity and cardiotoxicity assays lead to the discovery of compound ZM226 as a potent antitumor agent with low cardiotoxicity. These findings suggest optimization of arenobufagin on position 3 maybe an efficacious strategy for the development of antitumor drug candidates derived from arenobufagin.