Generation and Reactivity of DNA Cleaving Agents

近年来，人们对天然产物及其衍生物与DNA的反应进行了积极的研究。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。此外，这些知识不仅为靶向DNA的抗肿瘤药物的分子机制提供了依据，而且为癌症研究提供了基础信息。Ptaquiloside是从蕨类植物Pteridium aquilinum var. latiusculum中分离出来的一种强效致癌化合物。在弱碱性条件下产生的蕨菜终极致癌物是对氨基酸和核酸碱基的强烷基化剂，并引起DNA的裂解。利用脱氧四核苷酸d(GTAC)，我们揭示了最终致癌物与DNA切割的分子机制：1)最终致癌物通过DNA中腺嘌呤的N-3或鸟嘌呤的N-7形成共价加合物，并打开环丙烷环；2)n -糖苷键的自发切割主要发生在修饰的腺嘌呤上，以产生基位；3)基位非常不稳定，随后通过b消除反应发生骨干断裂。我们设计并合成了简单的蕨菜终极致癌物类似物，发现这些类似物比蕨菜终极致癌物稳定得多，并且具有与蕨菜终极致癌物相当的DNA切割活性。从海藻中分离出的三溴乙酰胺对一种具有粘附性的海洋细菌具有生长抑制作用。我们发现三溴乙酰胺具有细胞毒性，并研究了结构-细胞毒性关系。此外，三溴乙酰胺被证明是微管蛋白聚合的抑制剂。

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.