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Generation and Reactivity of DNA Cleaving Agents

DNA 切割剂的生成和反应性

基本信息

批准号：
10480149
负责人：
KIGOSHI Hideo
金额：
$ 4.67万
依托单位：
Nagoya 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 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10480149/
关键词：
DNA cleavage DNA alkylation Bracken fern Alga

项目摘要

Recently, reactions of natural products and their derivations toward DNA have been actively investigated. These researches provide molecular recognition of organic compounds toward DNA as well as structures and functions of DNA. Furthermore, this knowledge provides not only molecular mechanism of antitumor agents targetting DNA but also fundamental information to the cancer research.Ptaquiloside is a potent carcinogenic compound isolated from the bracken fern Pteridium aquilinum var. latiusculum. The bracken ultimate carcinogen generated from under weakly basic conditions acts as a powerful alkylating agent toward amino acids and nucleic acid bases, and causes cleavage of DNA. Using deoxytetranucleotide d(GTAC), we disclosed the molecular mechanism of DNA cleavage with the ultimate carcinogen : i) the bracken ultimate carcinogen forms covalent adducts through N-3 of adenin or N-7 of guanine in DNA with opening of the cyclopropane ring, ii) spontaneous cleavage of the N-glycosidic linkage occurs primarily at the modified adenines to produce abasic sites, and iii) the abasic sites are so unstable that subsequent backbone breakage occurs via a b-elimination reaction.We designed and synthesized simpler analogs of the bracken ultimate carcinogen, and found that these analogd are much more stable than the bracken ultimate carcinogen and possesses DNA cleaving activity comparable to that of the bracken ultimate carcinogen.A tribromoacetamide, isolated from a marine alga, exhibits a growth-inhibitory against a marine bacterium with an adhering property. We have found that tribromoacetamides have cytotoxicity, and studied of structure-cytotoxicity relationships. Furthermore, tribromoacetamides proved to be an inhibitor of tubulin-polymerization.

最近，人们积极研究天然产物及其衍生物与DNA的反应。这些研究提供了有机化合物对DNA的分子识别以及DNA的结构和功能。Ptaquiloside是从蕨属植物蕨菜Pteridium aquilinum var.阔肌在弱碱性条件下产生的蕨菜终极致癌物作为一种强有力的烷化剂作用于氨基酸和核酸碱基，并导致DNA裂解。使用脱氧四核苷酸d（GTAC），我们揭示了DNA切割与最终致癌物的分子机制：i）蕨菜最终致癌物通过DNA中腺嘌呤的N-3或鸟嘌呤的N-7与环丙烷环的打开形成共价加合物，ii）N-糖苷键的自发切割主要发生在修饰的腺嘌呤处以产生脱碱基位点，和iii）脱碱基位点是如此不稳定，以致随后通过b-消除反应发生主链断裂。我们设计并合成了蕨菜终极致癌物的更简单的类似物，发现这些类似物比蕨菜最终致癌物稳定得多，并且具有与蕨菜最终致癌物相当的DNA切割活性，从海洋细菌中分离的三溴乙酰胺对具有粘附特性的海洋细菌显示出生长抑制作用。我们发现三溴乙酰胺类化合物具有细胞毒性，并对其结构与细胞毒性的关系进行了研究。此外，三溴乙酰胺被证明是微管蛋白聚合的抑制剂。