Fibroblast Activation Protein α Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity
Fibroblast Activation Protein α Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity
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DOI：
10.1021/acs.jmedchem.6b01755
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发表时间：
2017-07-13
影响因子：
7.3
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
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作者：
Deng, Li-Juan;Wang, Long-Hai;Chen, Wei-Min
蟾毒二烯内酯类化合物是我国传统中药蟾酥的主要药理活性成分，在临床上被广泛应用于肿瘤的治疗。出于减少或避免蟾蜍二烯内酯的心脏毒性的动机，我们设计、合成并评估了成纤维细胞活化蛋白α（FAP α）活化的三肽arenobufagin前药，目的是提高arenobufagin（代表性蟾蜍二烯内酯）的安全性。在这些FAP α活化的前药中，3f表现出最佳的重组人FAP α（rhFAP α）水解效率，并在肿瘤中被活化。3f的LD_（50）是沙蟾毒精的6.5倍。我们还观察到，在超声心动图，心肌病理切片和乳酸脱氢酶活性（LDH）在3f治疗荷瘤小鼠，即使剂量达到使用的母体药物arenobufagin的量的3倍，也没有明显的变化。化合物3f在体外和体内也表现出显著的抗肿瘤活性。3f改善的安全性和有利的抗癌特性保证了对潜在临床意义的进一步研究。我们的研究表明，FAP α前药策略是成功增加蟾蜍二烯内酯类药物治疗窗口的有效方法。
Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein alpha (FAP alpha) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAP alpha-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAP alpha (rhFAP alpha) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAP alpha prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.