Synthesis of DNA-Binding Highly Functionalized Indole-alkaloid and Quinolone Derivatives and Their Function

1.合成（1）以吲哚-生物碱核为分子识别装置的新型DNA结合分子的合成：本研究通过多步反应高收率地合成了约30种新的β-咔啉衍生物和椭圆藤碱类似物。将N-甲基-N-亚硝基脲部分连接到β-咔啉或椭圆形碱核上作为嵌入剂。这两个结构之间的连接基由酰胺、醚或胺组成。连接基的长度为2 - 7个原子，并且连接基连接到β-咔啉的3-或9-原子和椭圆树碱的2-或5-原子。最后，通过染料-DNA键的线性二向色性或荧光各向异性确定了这些化合物与DNA的结合方式。（2）以1，6-萘啶核为分子识别装置合成新型DNA结合分子：以7-氟-1，6-萘啶衍生物为原料，高产率地合成了1，6-萘啶-甲基亚硝基脲的前体。此外，喹诺酮类、喹啉类、嘧啶类和1，3，8-三氮杂萘类化合物也是新的高产率合成方法。抗肿瘤活性的评价用肉瘤180、HeLa S-3和L1210细胞株对上述化合物进行了抗肿瘤活性的评价，结果显示抗肿瘤活性较高（IC_<50>&lt;1μM）。将N-甲基-N-亚硝基脲与N-甲基-N-亚硝基脲本身进行比较。反应主要生成N^3-甲基腺嘌呤和N^7-甲基鸟嘌呤。在前两个杂合化合物中，N^3-甲基腺嘌呤的形成增加。结果，小沟选择性提高（N-甲基-N-亚硝基脲的5-100倍）。

1.Synthesis(1)Synthesis of Novel DNA-Binding Molecules Using Indole-Alkalod Nucleus as Molecular-Recognizing Device :About thirty kinds of new β-carboline derivatives and ellipticine analogs were synthesized in high yield by multi step reactions in this study. The N-methyl-N-nitrosourea moiety was linked to the β-carboline or ellipticine nucleus as an intercalator. The linker between these two structures consists of amide, ether, or amine. The length of the linker was 2 - 7 atoms, and the linker was connected to the 3- or 9-atom of β-carboline and the 2- or 5-atom of ellipticine. Finally, Binding mode of these compounds to DNA was determined by linear dichroism or fluorescence anisotropy of dye-DNA firm, which is oriented by the chain alignment.(2)Synthesis of Novel DNA-Binding Molecules Using 1,6-Naphthyridine Nucleus as Molecular-Recognizing Device :The precursors of the 1,6-naphthyridine-methylnitrosoureas were synthesized from 7-fluoro-1,6-naphthyridine derivatives in high yields. In addition, quinolones, quinolines, pyrimidine, and 1,3,8-triazanaphthalenes were newly synthesized in high yields by efficient methods. Especially, synthesis of pyrimidines by four-component coupling reaction is completely new method, and bears watching.2.Evaluation of Antineoplastic AcitivityAntineoplastic activity of the compounds mentioned above was evaluated on the cell lines, Sarcoma 180, HeLa S-3, and L1210 to give high activity (IC_<50><1μM).3.Alkylation of DNA with DNA-Targeting Antineoplastic DrugDNA-methylation behavior of β-carboline- or ellipticine-N-methyl-N-nitrosourea was compared with that of N-methyl-N-nitrosourea itself. The reaction gave N^3-methyladenine and N^7-methylguanine as major products. In the former two hybrid compounds, the formation of N^3-methyladenine was increased. As a result, minor groove selectivity was enhanced (5-100 times of N-methyl-N-nitrosourea).