Hederacolchiside A1衍生物的合成及抗肿瘤活性研究

Synthesis and antitumor activity evaluation of hederacolchiside A1 derivatives

目的设计并合成哌嗪酰化和哌嗪磺酰化hederacolchiside A1衍生物,测试其对肿瘤细胞的抗增殖活性。方法采用半合成策略,在hederacolchiside A1的C-28位上引入磺酰化或甲酰化的哌嗪基团,同时在磺酰基和甲酰基上引入空间位阻大的芳香基团进行进一步结构修饰,得到两个系列的目标化合物(4a~4k和5a~5k)。以苯甲酰化和乙酰化的hederacolchiside A1为起始原料,经亲电取代、亲核取代反应得到含哌嗪基团的关键中间体,该中间体与含不同取代基的苯磺酰氯进行缩合反应得到目标化合物4a~4k;与含不同取代基的苯甲酰氯进行缩合反应得到目标化合物5a~5k。采用MTT法评价目标化合物的体外抗肿瘤活性。结果与结论设计并合成了22个未见文献报道的新化合物,其结构均经ESI-MS、^(1)H-NMR、^(13)C-NMR谱确证。体外抗肿瘤活性测试结果表明,化合物5e对MCF-7肿瘤细胞表现出较强的抗增殖活性,其IC50值为(4.89±0.09)μmol·L^(-1),优于阳性对照药hederacolchiside A1[IC_(50)=(19.36±0.48)μmol·L^(-1)]和5-氟尿嘧啶[IC_(50)=(26.14±1.76)μmol·L^(-1)],具有进一步研究的价值。

In order to discover new candidates with good antitumor activity,twenty-two compounds(4a-4k and 5a-5k)were designed and synthesized with hederacolchiside A1 as the lead compound using semisynthetic strategy to introduce piperazine moieties at C-28.The structures of target compounds were confirmed by ESI-MS,^(1)H-NMR and ^(13)C-NMR.With hederacolchiside A1 and 5-fluorouracil as the positive control drugs,all target compounds were evaluated for in vitro antitumor activities against human tumor cell lines as HCT116,A549,HL-60 and MCF-7 using the MTT colorimetric assay.The results showed that most of the hederacolchiside A1 derivatives containing formylated piperazine structures showed varying degrees of anti-proliferative activities against the tested tumor cell lines.Compound 5e exhibited excellent antiproliferation activity against MCF-7 cells with IC_(50) value of(4.89±0.09)μmol·L^(-1) compared with the positive control drugs,and it could be developed for further research.