1,2,7,9-四取代去氢骆驼蓬碱衍生物的合成及体外抗肿瘤活性

为了寻找高效低毒的抗肿瘤候选化合物, 以去氢骆驼蓬碱为原料, 对β-咔啉环的2-,7-和9-位3个结构位点进行了结构改造, 合成了11个去氢骆驼蓬碱衍生物, 化合物的结构经核磁共振、 红外光谱、 质谱及元素分析确证. 采用四甲基偶氮唑盐(MTT)法初步测试了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7)活性, 结果表明化合物4a, 4b, 8a和8b具有显著的体外抗肿瘤活性.

Synthesis and Biological Evaluation of 1,2,7,9-Tetrasubstituted Harmine Derivatives as Potential Antitumor Agents†

In order to search for novel candidate compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were synthesized by modiflcation of position 2, 7 and 9 of β-carboline nucleus through N9-alkylated, C7-demethylated and C7-phenolic hydroxyl alkylated. C7-demethylation compounds could be easily obtained from the N9-alkylated derivatives using acetic acid and hydrobromic acid as reaction solvent, but N9-arylted derivatives couldn’t get the demethylation compounds in the same way. The N2-quaternarized compounds(4a, 4b, 8a and 8b) were prepared from demethylation compounds(3a, 3b, 7a and 7b) by the addition of benzyl bromide in refluxing ethyl acetate. Eleven target compounds were synthesized and characterized by ¹H NMR, ¹³C NMR, IR, MS and elemental analysis. All the target compounds were tested for cytotoxic activity against six cancer cell lines including Bel-7402, 786-0, BGC-823, A375, 769-P and MCF7 by methyl thiazolyl tetrazolium(MTT) method in vitro. Structure-activity relationships studies confirmed that N2-quaternarized compounds(4a, 4b, 8a and 8b) had more remarkable cytotoxic activities in vitro than harmine.