原癌基因c-myc G-四链体配体甲基蓝衍生物的设计、合成及其活性研究

摘要

Using the computer-aided drug design method,the ligands designed with methyl blue as the lead compound were docked with the three-dimensional structure of G-quadruplexs formed by telomeric DNA,proto-oncogene c-myc and c-kit2. The ligand was found to selectively target the c-myc G-quadruplex with a docking score of 7. 74. The target compound was synthesized with phenoth-iazine as the starting material,its structure was characterized by 1 H-NMR,13 C-NMR and HRMS. The interaction of the target com-pound and DNA sequences including telomere,c-myc and c-kit2,was evaluated by circular dichroism spectroscopy. The results showed that the target compound selectively induced c-myc DNA to form G-quadruplex.%采用计算机辅助药物设计方法,将以甲基蓝为先导化合物设计的配体分子与端粒DNA、原癌基因c-myc、c-kit2等形成的G-四链体三维结构进行分子对接模拟,发现目标化合物选择性靶向c-myc G-四链体,其对接分值为7.74.以吩噻嗪为起始原料合成出目标化合物,其结构经1 H-NMR、13 C-NMR和HRMS等确证.采用圆二色光谱实验测试了化合物与端粒、原癌基因c-myc和c-kit2等DNA的相互作用,结果表明目标化合物选择性诱导c-myc DNA形成G-四链体.