Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

Automated summary

Novel 3,11-bispeptide ester derivatives of arenobufagin were designed and synthesized, and their in vitro antiproliferative activity was evaluated. The results showed that the moiety at C3 and C11 hydroxy had a significant impact on cytotoxic activity and selectivity. Compound ZM350 significantly inhibited tumor growth by 58.8% in an A549 nude mice xenograft model at a dose of 10 mg/kg. These findings suggest that the novel 3,11-bispeptide ester derivatives have the potential to be developed as antitumor agents.