Collaboration on DNA sequence-specific recognition by small molecules

小分子 DNA 序列特异性识别合作

• 批准号: 10044134
• 负责人: SUGIYAMA Hiroshi
• 金额: $ 6.72万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10044134/
• 关键词: Antitumor Agent; Sequence-specific recognition of DNA; DNA alkylation; Post genome; Pyrrole-imidazole polyamides; 抗がん剤; グルーブバインダー; 分子認識; DNA分子認識; DNA構造; NMR; X線構造解析; ブレオマイシン; 平行DNA

By the completion of the human genome project, many diseases including cancer, hereditary and viral diseases can be understood by the DNA sequence level. Control of the specific gene expression will provide ultimate gene therapy. Minor groove binding polyamides containing N-methylpyrrole and N-methylimidazole amino acids exhibit promising performance based on the recognition of nucleic acid sequences. Various types of sequence-specific DNA binding agents are developed and used for the regulation of gene expression. In this collaboration, we synthesized novel type of polyamide-alkylator conjugates and unnatural DNA and investigated molecular basis of sequence specific recognition by small molecules including pyrrole-imidazole polyamides. These synthetic compounds alkylated predetermined DNA sequences selectively, and also some of them possessed selective potency for certain cancer cell lines. One of the future directions of rational design of molecular medicine in the post genome era is proposed.

随着人类基因组计划的完成，包括癌症、遗传病和病毒性疾病在内的许多疾病都可以从DNA序列水平上得到理解。对特定基因表达的控制将提供最终的基因治疗。含有N-甲基吡咯和N-甲基咪唑氨基酸的微小沟槽结合聚酰胺在识别核酸序列方面表现出良好的性能。各种类型的序列特异性DNA结合剂被开发并用于基因表达的调节。在这次合作中，我们合成了新型的聚酰胺-烷基化偶联物和非天然DNA，并研究了包括吡咯-咪唑聚酰胺在内的小分子对序列特异性识别的分子基础。这些合成的化合物选择性地烷基化预定的DNA序列，其中一些化合物对某些癌细胞株也具有选择性效力。提出了后基因组时代分子医学合理设计的未来方向之一。

项目成果

Yang,X.-L.,Ikeda,S.,Saito,I.,Wang,A.H.-J.Sugiyama,H.,: "Structural Studies of a Stable Paralles-Stranded DNA Duplex Incorporating Isoguanine : Cytosine and Isocytosine : Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy."Biophysical Journal. 75

Yang，X.-L.，Ikeda，S.，Saito，I.，Wang，A.H.-J.Sugiyama，H.，：“掺入异鸟嘌呤的稳定平行链 DNA 双链体的结构研究：胞嘧啶和异胞嘧啶：鸟嘌呤碱基对

Tao,Z.-F.,Saito,I.,Sugiyama,H.: "Highly cooperative DNA dialkylation by the homodimer of imidazole-pyrrole diamide-CPI conjugate with vinyl linker"J.Am.Chem.Soc.. 122. 1602-1608. (2000)

Tai, Z.-F., Saito, I., Sugiyama, H.：“通过带有乙烯基连接基的咪唑-吡咯二酰胺-CPI 缀合物的同二聚体进行高度协同的 DNA 二烷基化”J.Am.Chem.Soc.. 122. 1602

Tao, Z.-F. ; Saito, I. ; Sugiyama, H.: "Highly Coorperative Dialkylation by the Homodimer of Imidazole-Pyrrole Diamide-CPI Conjugate."J.Am.Chem.Soc.. 122. 1602-1608 (2000)

陶，Z.-F。

Kawai, K.; Saito, I.; Sugiyama, H.: "Photochemical Halogen-Exchange Reaction of 5-lodouracil-Containing Oligonucleotides."Tetrahedron Letters. 40. 5721-5724 (1999)

卡瓦伊，K.；

Yang, X.-L.; Hubbard IV, R. B.; Lee, M.; Tao, Z.-F.; Sugiyama, H.; Wang, H.-J.: "Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs."Nucleic Acids Res.. 27. 4183-4190 (1999)

杨，X.-L.；