4β-芳香酰胺类鬼臼毒素衍生物的合成及体外抗肿瘤活性研究

Synthesis and evaluation of 4β-aromatic amide podophyllotoxin derivatives as potential antitumor agents

【目的】通过鬼臼毒素母核C-4位的酰胺化,以获得高效、低毒、抗多药耐药的新型酰胺类鬼臼毒素衍生物。【方法】将4β-氨基-4-脱氧表鬼臼毒素和4'-去甲基-4β-氨基-4-脱氧表鬼臼毒素的C-4位经酰胺化,分别引入小分子芳香羧酸:2-氯异烟酸、6-氯吡啶-3-乙酸、4-苯氧基苯甲酸以及4-苯氧基苯乙酸,得到C-4位为不同酰胺基团的鬼臼毒素类衍生物,通过MTT法筛选,对K562和Hela细胞进行药理活性评价。【结果】合成得到A、B两个系列共8个化合物,所有化合物都经过HRESI-MS、1HNMR和13CNMR验证,其中化合物A1、B1、B3具有较强的体外抗肿瘤活性,且优于阳性对照药物Etoposide(VP-16)。【结论】(1)鬼臼毒素C-4'位羟基的游离性对其发挥体外细胞毒活性很关键。(2)鬼臼毒素C-4位成酰胺可显著影响其体外抗肿瘤活性。

[Objective]To obtain new podophyllotoxin derivatives with higher efficiency, lower toxicity and anti-multi-drug resistance. [ Methods] Introduce 2-Chloroisonicotinie, 2-Chloropyridine-5-aeetieacid, 4-Phenoxybenzoic acid and 4-Phenoxy phenylcaetie acid in C-4 position of 4β-amino-pipodophyllotoxin; Hela cells and K562 were used to evaluate pharmacological activity in vitro. [ Results ] Obtained two series about 8 compounds, all compounds were confirmed by HR-ESI-MS, 1HNMR and 13CNMR validation. The compounds A1, B 1, B3 had a better drug-resistant activity in both Hela and K562 cell line than Etoposide （VP-16）. [ Conclusion ] （1） C-4＇-OH is crucial; （2） C-4 amide group can obviously influence its antitumor activity in vitro.