青藤碱-硝酸酯偶联物的合成及体外抗肿瘤活性筛选

Synthesis and in vitro anti-tumor effects screening of sinomenine-nitrate conjugates

目的:为寻找青藤碱有效的结构修饰方法以挖掘其抗肿瘤作用。方法:基于对母体结构特点的剖析设计合成了一系列青藤碱-硝酸酯偶联物,所合成偶联物的结构经IR光谱、^(1)H-NMR、^(13)C-NMR和高分辨质谱确证。运用四甲基偶氮唑蓝(MTT)法筛选偶联物对人源5种肿瘤细胞(宫颈癌Hela细胞、肺癌A549细胞、肝癌HepG2细胞、乳腺癌MCF-7细胞和结肠癌HT-29细胞)体外抗肿瘤活性。结果:共设计合成了9个青藤碱-硝酸酯偶联物。相比其他系列的偶联物,6-苯腙基青藤碱-硝酸酯偶联物体外抗肿瘤作用更为突出,其中衍生物10d对Hela,MCF-7及HT-29细胞株的抑制作用均优于阳性对照药顺铂,IC_(50)分别为(9.72±0.53),(15.46±8.16),(8.19±1.05)μmol·L^(-1)。结论:衍生物10d对多种待测肿瘤细胞有良好的体外抗肿瘤活性,可作为抗肿瘤的前体药物分子,值得继续开展进一步的研究。

Objective:To find effective structural modification methods for discovering the anti-tumor activity of sinomenine.Methods:Based on the structural characteristics of sinomenine,a series of sinomenine-nitrate conjugates were designed and synthesized.The structures of all these compounds were confirmed by infrared spectroscopy,nuclear magnetic resonance hydrogen spectroscopy,nuclear magnetic resonance carbon spectroscopy and high-resolution mass spectrometry.MTT assay was used to test the inhibitory effects of sinomenine-nitrate conjugates on the proliferation of human tumor cells(cervical cancer Hela cells,lung cancer A549 cells,liver cancer HepG2 cells,breast cancer MCF-7 cells and colon cancer HT-29 cells) in vitro.Results:Nine nitrate derivatives were effectively synthesized.Compared with other conjugates,6-phenylhydrazone sinomenine-nitrate conjugates showed outstanding anti-tumor activity in vitro.The anti-proliferation ability of derivative 10d on Hela,MCF-7 and HT-29 was better than that of the positive drug cisplatin,with IC_(50) being(9.72±0.53),(15.46±8.16),(8.19±1.05) μmol·L^(-1),respectively.Conclusion:Compound 10d has good anti-tumor activity against various tested tumor cells and can be used as a precursor molecule for anti-cancer drugs,which needs to be further studied.