Development of Porphyrin as a Molecular Cutter of Genes

卟啉作为基因分子切割剂的开发

• 批准号: 13557199
• 负责人: UNO Tadayuki
• 金额: $ 8.96万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557199/
• 关键词: Porphyrin; Photonuclease; Resonance Ramen Spectroscopy; Telomere; DNA

In this project, we designed and synthesized novel water-soluble poiphyrins based on our previous research, and intended to develop DNA-cleaving reagent specific to base sequences, through the measurement of DNA-cleaving activity against DNA having various base sequences. The activity was found to be greatly enhanced by zinc insertion into the porphyrin core, and the effect of copper insertion was also examined. The binding property of copper porphyrin with DNA was examined by absorption and resonance Raman spectroscopic technique, and the self stacking of porphyrin was found to be enhanced by the flattening of the porphyrin macrocycle. This in mind, the porphyrin was applied to the inhibition of telomerase activity, expecting to be an anti-cancer drug. Human telomere is composed of thousands of repeats of TTAGGG sequence, and quadruplex structure is produced. The binding property of the copper porphyrin with this sequence was examined, and the external stacking of the porphyrin was suggested. The copper porphyrin greatly stabilized the quadruplex structure, and the inhibition of telomerase activity was strongly suggested. We further synthesized several kinds of porphyrins having long cationic peripheries on the macrocycle. These poiphyrins stabilized the quadruplex similarly, and therefore the cationic groups were supposed to contribute greatly in the binding. In conclusion, we could synthesize porphyrin drugs which bind specifically to a sequence-dependent DNA structure, recognize the structure, and bind selectively.

在本课题中，我们在以往研究的基础上，设计合成了新型的水溶性卟啉类化合物，并通过测定对各种碱基序列的DNA的切割活性，开发对碱基序列特异的DNA切割试剂。发现锌插入到卟啉核中大大增强了活性，并且还检查了铜插入的效果。用吸收光谱和共振拉曼光谱研究了铜卟啉与DNA的结合性质，发现卟啉大环的扁平化增强了卟啉的自堆积.考虑到这一点，卟啉被应用于抑制端粒酶活性，有望成为一种抗癌药物。人类端粒由数千个TTAGGG序列重复组成，并产生四链体结构。研究了铜卟啉与该序列的结合性质，并提出了卟啉的外堆积。铜卟啉大大稳定了四链体结构，并强烈建议抑制端粒酶活性。我们进一步合成了几种在大环上具有长阳离子外围的卟啉。这些卟啉类似地稳定了四链体，因此阳离子基团被认为在结合中有很大贡献。总之，我们可以合成卟啉药物，它可以特异性地结合到依赖于序列的DNA结构上，识别结构，并选择性地结合。

项目成果

Yoshinobu Ishikawa, Takeshi Yamashita, Yoshikazu Tomisugi, and Tadayuki Uno: "Interaction of porphyrins bearing peripheral cationic heterocycles with G-quadruplex DNA"Nucleic Acids Res.. Suppl.1. 107-108 (2001)

Yoshinobu Ishikawa、Takeshi Yamashita、Yoshikazu Tomisugi 和 Tadayuki Uno：“带有外周阳离子杂环的卟啉与 G-四链体 DNA 的相互作用”核酸研究补充材料 1。

Yoshinobu Ishikawa: "Potent DNA Photocleavage by Zinc(II) Complexes of Cationic Bis-porphyrins Linked with Aliphatic Diamine"Bioorg.Med.Chem.. 10. 1953-1960 (2002)

Yoshinobu Ishikawa：“通过与脂肪族二胺连接的阳离子双卟啉的锌 (II) 复合物进行有效的 DNA 光裂解”Bioorg.Med.Chem.. 10. 1953-1960 (2002)

Yoshinobu Ishikawa, Naoki Yamakawa, and Tadayuki Uno: "Potent DNA Photocleavage by Zinc(II) Complexes of Cadonic Bis-porphyrins Linked with Aliphatic Diamine"Bioorg. Med. Chem.. 10. 1953-1960 (2002)

Yoshinobu Ishikawa、Naoki Yamakawa 和 Tadayuki Uno：“与脂肪族二胺连接的钙双卟啉锌 (II) 复合物对 DNA 的有效光裂解”Bioorg。

Yoshinobu Ishikawa: "Interaction of porphyrins bearing peripheral cationic heterocycles with G-quadruplex DNA"Nucleic Acids Res.Suppl.. 1. 107-108 (2001)

Yoshinobu Ishikawa：“携带外周阳离子杂环的卟啉与 G-四链体 DNA 的相互作用”Nucleic Acids Res.Suppl.. 1. 107-108 (2001)

Naoki Yamakawa: "Solution Properties and Photonuclease Activity of Cationic Bis-porphyrins Linked with a Series of Aliphatic Diamines"Chem.Pharm.Bull.. 49. 1531-1540 (2001)

Naoki Yamakawa：“与一系列脂肪族二胺连接的阳离子双卟啉的溶液性质和光核酸酶活性”Chem.Pharm.Bull.. 49. 1531-1540 (2001)