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

1.合成(1)以吲哚-碱核为分子识别装置合成新型β结合分子：本研究通过多步反应，高产率地合成了近30种新的DNA-咔啉衍生物和椭圆碱类似物。N-甲基-N-亚硝脲部分作为插层剂连接到β-Caroline或椭圆形核上。这两种结构之间的连接物由酰胺、乙醚或胺组成。连接体的长度为2-7个原子，连接体连接到β-Caroline的3-或9-原子和椭圆碱的2-或5-原子。最后，通过染料-DNA骨架的线性二色性或荧光各向异性来确定它们与DNA的结合方式。(2)以1，6-萘啶为分子识别元件合成新型DNA结合分子：以7-氟-1，6-萘啶为原料，高产率地合成了1，6-萘啶-甲基亚硝脲的前体。此外，还通过有效的方法高产率地合成了喹诺酮类、喹啉类、嘧啶类和1，3，8-三氮杂萘类化合物。其中，四组分偶联反应合成嘧啶类化合物是一种全新的方法，值得关注。2.抗肿瘤活性的评价上述化合物的抗肿瘤活性分别在S_(180)、HeLa_(S-3)和L1210细胞(IC_&lt；50&gt；&lt；1μM)上进行了评价。3.比较了β-咔啉或椭圆碱-N-甲基-N-亚硝脲本身的抗肿瘤活性。反应主要产物为N^3-甲基腺嘌呤和N^7-甲基鸟嘌呤。在前两种杂化化合物中，N^3-甲基腺嘌呤的生成增加。结果表明，微槽选择性得到提高(是N-甲基-N-亚硝脲的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).