Design and synthesis of novel 20(S)-α-aminophosphonate derivatives of camptothecin as potent antitumor agents

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.