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.

中文翻译：

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发现具有体内抗肿瘤活性和降低心脏毒性潜力的新型 3,11-双肽酯沙蟾毒苷衍生物

沙蟾毒精是从中药蝉速中分离出来的蟾蜍二烯内酯之一，具有强大的抗肿瘤活性。然而，严重的毒性和小的治疗窗限制了其药物开发。在本研究中，据我们所知，在我们先前发现的具有活性的3-单肽酯衍生物的基础上，首次设计并合成了新型3,11-双肽酯槟榔衍生物。体外抗增殖活性评价表明，C3 和 C11 羟基部分对细胞毒活性和选择性有重要影响。化合物ZM350在 A549 裸鼠异种移植模型中以 10 mg/kg 的剂量显着抑制肿瘤生长 58.8%。因此，复配ZM350还呈现出浓度依赖性细胞凋亡诱导和对 hERG 钾通道和 Cav1.2 钙通道的低抑制作用。我们的研究表明，新型 3,11-双肽酯衍生物将有利于进一步开发砂蟾毒精的抗肿瘤剂。