双-β-咔啉衍生物的设计、合成及抗肿瘤活性

以去氢骆驼蓬碱为原料, 经过脱甲基、 烷基化等步骤, 合成了一系列双-β-咔啉衍生物. 目标化合物均经核磁共振谱(NMR)和质谱(MS)进行结构确证. 以顺铂为阳性对照药, 采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7等6株细胞)活性. 结果表明, 化合物4g和4o与阳性对照药相比具有良好的抗肿瘤活性, 其半抑制浓度(IC₅₀)值均小于10 μmol/L. 初步构效关系研究表明, 当桥链亚甲基数目为8~10, β-咔啉环上9-丁基或9-异丁基取代时, 化合物的抗肿瘤活性较强.

Design,Synthesis and in vitro Antitumor Activities of Novel Bivalent β-Carbolines†

A series of novel bivalent β-carbolines with a spacer of three to ten methylene units between the 7-oxygen was synthesized and characterized by nuclear magnetic resonance(NMR) and mass spectrometry(MS). The antitumor activities against Bel-7402, 786-0, BGC-823, A375, 769-P and MCF7 cell lines in vitro were investigated by MTT method. The results demonstrated that compounds 4c, 4k and 4r were almost inactive against all tumor cell lines, compounds 4g and 4o displayed significant cytotoxic activities with IC₅₀ value of lower than 10 μmol/L against all tumor cell lines. Most compounds displayed good and selective cytotoxic activities against HT-29 and Blu-87 cell lines. Primary structure-activity relationships(SARs) analysis indicated that the length of the spacer affected cytotoxic activities in vitro, and 8—10 methylene units were more favorable. Moreover, n-butyl or i-butyl substituents in position-9 of β-carboline facilitated the antitumor potencies.