12-[N-酰基氨甲基]-14-去氧穿心莲内酯衍生物的合成及抗肿瘤活性

Synthesis and antitumor activity of 12-[N-acylaminomethyl]-14-deoxyandrographolide derivatives

在中药穿心莲主要有效成分穿心莲内酯的12位引入N-酰基氨甲基,合成一系列衍生物,并研究其抗肿瘤活性。在甲醇钠作用下,穿心莲内酯(1)与硝基甲烷进行Michael加成反应,重排生成12-硝基甲基-14-去氧穿心莲内酯(2),再以锌粉盐酸还原硝基生成12-氨基甲基-14-去氧穿心莲内酯(3),最后以HOBt和EDC催化缩合羧酸反应生成一系列目标酰胺(4)以及与磺酰氯反应生成磺酰胺(5);制备的穿心莲内酯衍生物(4a～4n和5a～5c)的结构经质谱和磁共振谱分析证实。初步的抗肿瘤活性筛选显示制得的化合物抗肿瘤活性较弱;12位引入较长亲水基团可能会导致抗肿瘤活性降低。

Andrographolide is one of the main active constituent of Andrographis paniculata.Many studies have been done on its structural modification in order to improve the potency.In this paper,a series of andrographolide derivatives with the structure of 12-[N-acyl aminomethyl]-14-deoxyandrographolide were synthesized starting from the parent compound andrographolide via Michael addition,reduction and amidation reactions.All the compounds were identified by MS and NMR analysis.Their antitumor activities were preliminarily tested on cancer cell lines U87 and MCF-7 by MTT method.However,none of the tested compunds was more potent than the parent compound,suggesting that the long alkyl chains introduced to C-12 of andrographolide might decrease the antitumor activity.