Cell-biological analysis of sequence-specific DNA alkylating molecules.

序列特异性 DNA 烷基化分子的细胞生物学分析。

• 批准号: 20710164
• 负责人: KEN-ICHI Shinohara
• 金额: $ 2.66万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20710164/
• 关键词: テロメア; 核酸; Py-Imポリアミド; 細胞老化; DNAアルキル化; PIポリアミド; 白血病

We designed and synthesized alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates. The effects on telomere shortening and growth inhibition were investigated using human cancer cell lines. In addition, we modified the DNA alkylating moiety CBI to the chlorambucil, which are easier to synthesize from commercially available components. The sequence-specific DNA alkylations by the chlorambucil conjugates were observed, which were as efficient as their of the CBI conjugates. The chlorambucil conjugates recognized 11 bp of telomere sequence specifically. However, the growth inhibiting activities were relatively reduced compared with CBI conjugates. Thus, these low-toxic and highly efficient DNA alkylating molecules should be more useful for investigation of their gene regulating activities and study of DNA-damage responses.

我们设计并合成了烷基化N-甲基吡咯-N-甲基咪唑（PI）聚酰胺缀合物。使用人癌细胞系研究了对端粒缩短和生长抑制的影响。此外，我们将DNA烷基化部分CBI修饰为苯丁酸氮芥，这更容易从市售成分合成。观察到苯丁酸氮芥缀合物的序列特异性DNA烷基化，其与CBI缀合物一样有效。苯丁酸氮芥结合物特异性识别11 bp的端粒序列。然而，与CBI缀合物相比，生长抑制活性相对降低。因此，这些低毒高效的DNA烷基化分子在研究其基因调控活性和DNA损伤反应方面将具有更大的应用价值。

项目成果

Chiral wedge molecule inhibits telomerase activity

手性楔形分子抑制端粒酶活性

• 发表时间: 2007
• 作者: M. Kopec;A. Yamada;G. Kobayashi;S. Nishimura;R. Kanno;A. Mauger;F. Gendron;C.M. Julien;杉山弘
• 通讯作者: 杉山弘

テロメアを標的とするピロール-イミダゾールポリアミド

靶向端粒的吡咯-咪唑聚酰胺

• 发表时间: 2008
• 作者: 篠原憲一;蓑島維文;板東俊和;杉山弘
• 通讯作者: 杉山弘

Anticancer Activities of Alkylating Pyrrole-Imidazole Polyamides with Specific Sequence Recognition

具有特定序列识别功能的烷基化吡咯-咪唑聚酰胺的抗癌活性

• 发表时间: 2010
• 期刊: Anti-Cancer Drug 21
• 作者: Ken-ichi Shinohara;Toshikazu Bando;Hiroshi Sugiyama
• 通讯作者: Hiroshi Sugiyama

Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI

• DOI: 10.1016/j.bmc.2009.12.033
• 发表时间: 2010-02-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Minoshima, Masafumi;Bando, Toshikazu;Sugiyama, Hiroshi
• 通讯作者: Sugiyama, Hiroshi

Cooperative alkylation of double-strand human telomere repeat sequences by PI polyamides with 11-base-pair recognition based on a heterotrimeric design.

• DOI: 10.1016/j.bmc.2008.12.019
• 发表时间: 2009-02
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Gengo Kashiwazaki;T. Bando;K. Shinohara;Masafumi Minoshima;S. Nishijima;H. Sugiyama