<i>N</i>-苄氧羰基甘氨酰-L-脯氨酸-鬼臼毒素衍生物的合成及其抗肿瘤活性

N-苄氧羰基甘氨酰-L-脯氨酸-鬼臼毒素衍生物的合成及其抗肿瘤活性

摘要: 以鬼臼毒素（podophyllotoxin）、N-苄氧羰基甘氨酰-L-脯氨酸为原料，首次合成了10个新型鬼臼毒素衍生物（Ⅲa ~ Ⅲi、Ⅳ），目标化合物结构经¹H NMR、¹³C NMR和MS确认。采用MTT法测试化合物Ⅲa ~ Ⅲi和Ⅳ对HepG2、THP-1、HeLa、MCF-7细胞的抑制活性。结果表明：所有目标化合物均具有不同程度的抑制活性，其中化合物Ⅲa对HepG2细胞的活性最突出，IC₅₀达0.58 nmol/L。通过分子对接模拟技术进一步研究了化合物Ⅲa和FAPα酶的结合模式，Ⅲa可以与FAPα酶的多个位点产生相互作用，值得进一步研究其抗肿瘤机制。

Abstract: Ten novel podophyllotoxin derivatives (IIIa-IIIi and IV) were synthesized by three-step reactions using podophyllotoxin and N-benzyloxycarbonyl glycine-L-proline as raw material. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR and MS. MTT method was used to test anti-tumor activity of the target compounds on HepG2, THP-1, HeLa and MCF-7 cells. The results showed that all the target compounds had inhibitory activity against HepG2, THP-1, HeLa and MCF-7 cells, and the inhibitory activity of IIIa on HepG2 cells was the most prominent with an IC₅₀ value of 0.58 nmol/L. The binding mode of compound IIIa and FAPα was studied by molecular docking. Compound IIIa could bind to multiple sites of FAPα enzyme.