4'-去甲基表鬼臼毒素芳香酰胺类衍生物的设计、合成及其抗肿瘤活性

Synthesis and antitumor activity of 4'-demethylepipodophyllotoxin aromatic amide derivatives

目的为寻找高效低毒且作用谱广的鬼臼脂素类抗肿瘤药物,合成了20个4'-去甲基表鬼臼毒素芳香酰胺类化合物。方法以4'-去甲基表鬼臼毒素为原料,首先与氯乙腈进行取代反应,再与硫脲反应,最后与不同的取代芳香羧酸成酰胺制得目标化合物。采用MTT法测定目标化合物体外对人肺腺癌细胞A549、人肝肿瘤细胞株HepG2、人口腔癌KB细胞、L1210白血病细胞的抑制活性。结果与结论合成了20个未见文献报道的新化合物,目标化合物的结构均经~1H-NMR和MS谱确证,活性测试结果表明,大部分目标化合物均具有一定的肿瘤细胞增殖抑制活性。

In order to find the novel epipodophyllotoxins antitumor drugs and reduce toxicity and side effect, twenty novel 4＇-demethylepipodophyllotoxin aromatic amide derivatives were designed and synthesized. Amino groups were introduced by Ritter reaction, and different side chains were introduced by condensation reaction. All of them have been characterized by 1H-NMR and ESI-MS, and the effects of synthesized compounds against proliferations of A549, HepG2, KB, L1210 cells were evaluated by MTT test. The introduction of halogen in thiophene ring can increase the inhibition of A549, KB, L1210 cells; the introduction of halogen in indole ring can decrease the inhibition activity, however, the introduction of electron-donating group, such as methoxyl group can increase the inhibitory activity; carbon chain elongation can decease the inhibitory activity.