白杨素甘氨酸类化合物的合成及抗癌活性

以白杨素为起始原料, 通过卤代和水解反应制得中间产物7-O-羧烷基化的白杨素衍生物(6~9); 然后以1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDCI)、 1-羟基苯并三氮唑(HOBt)和4-二甲氨基吡啶(DMAP)为催化体系, 4个中间产物分别与甘氨酸甲酯盐酸盐进行酰胺缩合反应, 制得白杨素甘氨酸甲酯类化合物12~15; 化合物12~15在pH=10~11和室温下水解得到相应的白杨素甘氨酸类化合物(16~19). 所有目标化合物的结构均经 ¹H NMR, ¹³C NMR, IR以及MS确认. 以顺铂为阳性对照药物, 采用噻唑蓝比色(MTT)法检测了目标化合物对人肝癌细胞HepG2和人胃癌细胞MGC-803的体外增殖抑制作用. 结果表明, 目标化合物14~16, 18和19的体外抗肿瘤活性明显强于白杨素, 且化合物18(IC₅₀=4.36 μmol/L)对MGC-803细胞的增殖抑制作用强于阳性药物顺铂(IC₅₀=4.40 μmol/L).

Syntheses and Anticancer Activities of Glycine Derivatives of Chrysin†

In order to obtain novel lead compounds with high efficacy, low toxicity and minimum of side effects, using chrysin(5,7-dihydroxyflavone) with very broad biological activities as a starting material, four intermediates 7-O-carboxyalkylation chrysin derivatives(6—9) were synthesized by halogenation and hydrolysis. Four glycine methyl ester derivatives containing chrysin(12—15) were synthesized when the four intermediates above condensated with glycine methyl ester hydrochloride using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDCI), N-hydroxybenzotriazole(HOBt) and 4-dimethylamiopryidine(DMAP) as a coupling reagent. And then the corresponding glycine derivatives of chrysin(16—19) were obtained by hydrolysis under conditions of room temperature and pH 10—11. The structures of the target compounds were assigned by ¹H NMR, ¹³C NMR, IR and MS. Taking cisplatin as a reference substance, the in vitro antitumor activity tests for target compounds against human hepatocellular carcinoma HepG2 cells and gastric carcinoma MGC-803 cells were carried out by MTT method. The results of primary pharmacological tests indicated that five compounds(14—16, 18, 19) possessed the more potent antitumor activity than chrysin in vitro. What’s more, the antitumor activity of compound 18(IC₅₀=4.36 μmol/L) against MGC-803 cells was better than the positive reference compound cisplatin(IC₅₀=4.40 μmol/L).