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

DNA结合高功能化吲哚生物碱和喹诺酮衍生物的合成及其功能

基本信息

批准号：
16550148
负责人：
KONAKAHARA Takeo
金额：
$ 2.37万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

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).

1.合成(1)以吲哚碱核为分子识别装置合成新型DNA结合分子：本研究通过多步反应高产率合成了约30种新型β-咔啉衍生物和玫瑰树碱类似物。 N-甲基-N-亚硝基脲部分作为嵌入剂与β-咔啉或玫瑰树碱核连接。这两个结构之间的连接基由酰胺、醚或胺组成。连接子的长度为2-7个原子，并且连接子与β-咔啉的3-或9-原子和玫瑰树碱的2-或5-原子连接。最后，通过链排列定向的染料-DNA膜的线性二色性或荧光各向异性来确定这些化合物与DNA的结合模式。(2)使用1,6-萘啶核作为分子识别装置合成新型DNA结合分子：1,6-萘啶-甲基亚硝基脲的前体是由 7-氟-1,6-萘啶衍生物以高产率合成。此外，还通过高效方法高产率地新合成了喹诺酮类、喹啉类、嘧啶类和1,3,8-三氮萘类化合物。特别是通过四组分偶联反应合成嘧啶是全新的方法，值得关注。2.抗肿瘤活性评价上述化合物的抗肿瘤活性在细胞系Sarcoma 180、HeLa S-3和L1210上进行了评价，显示出高活性(IC_<50><1μM)。3.DNA靶向抗肿瘤对DNA的烷基化将 β-咔啉-或玫瑰树碱-N-甲基-N-亚硝基脲的药物 DNA 甲基化行为与 N-甲基-N-亚硝基脲本身的药物 DNA 甲基化行为进行了比较。反应得到N^3-甲基腺嘌呤和N^7-甲基鸟嘌呤作为主要产物。在前两种杂化化合物中，N^3-甲基腺嘌呤的形成增加。结果，小沟选择性得到增强（N-甲基-N-亚硝基脲的5-100倍）。