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Development of Anticancer Agents Based on Photochemical DNA-Cleavage

基于光化学 DNA 切割的抗癌剂的开发

基本信息

批准号：
12557202
负责人：
SHIBUYA Masayuki
金额：
$ 8.45万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557202/
关键词：
enediyne enyne-allene synthesis lexitropsin radical optically-active DNA cleavage ハロゲン

项目摘要

Various acyclic (Z)-1, 2, 4-heptatrien-6-ynes, which undergo cycloaromatization to produce reactive dehydrotoluene biradicals, have been investigated as chemical models for a class of potent antitumor antibiotics, neocarzinostatin (NCS). The preparation of enyne-allene models possessing characteristic triggering devices which initiate the generation of dehydrotoluene biradicals is a challenging current problem. For the development of this class of molecules, we designed various models which produce carbon-biradicals via Myers-Saito-type cyclization. For typical examples, we synthesized the naphthoate esters having the α-hydroxy naphthoate moiety in NCS and demonstrated the biradical formation reactions in acidic media.For the elucidation of these cascade reaction mechanisms and development of biologically active substances, the preparation of thermally stable carboxylic acid derivatives, which cycloaromatize under mild conditions, is essential. For this purpose, we designed novelα-alkynylacetic acid derivatives. A series of decarboxylative cycloaromatization reactions under various conditions were carried out. The reaction rates in MeOH were relatively slow and the reactions in the absence or presence of a radical scavenger (O_2 or 1, 4-cyclohexadiene) produced the products in similar yields, respectively. These results suggest that the cycloaromatization proceeded via an ionic cyclization pathway but not via the biradical intermediate.In order to prevent the ionic pathway during the cyclization reaction, the molecules possessing electron-withdrawing groups which destabilize the cationic carbon center were synthesized. The reactions of these compounds in acidic media produced predominantly or exclusively the products via biradical intermediates. Some of them showed relatively potent DNA-damaging activity. Studies on the analogues of this class of compounds and development of bio-active enediynes are continuing.

各种无环（Z）-1，2，4-庚三烯-6-炔化合物通过环芳构化反应生成反应性的脱氢甲苯双自由基，已被研究作为一类有效的抗肿瘤抗生素新癌抑制素（NCS）的化学模型。烯炔-联烯模型的制备具有引发脱氢甲苯双自由基生成的特征触发装置，是当前具有挑战性的问题。为了开发这类分子，我们设计了各种模型，通过Myers-Saito型环化产生碳双自由基。为了阐明这些级联反应的机理和开发具有生物活性的物质，制备热稳定的羧酸衍生物并在温和条件下进行环芳构化是必不可少的。为此，我们设计了新型α-炔基乙酸衍生物。在不同条件下进行了一系列脱羧环芳构化反应。在甲醇中反应速率较慢，在无自由基清除剂（O_2或1，4-环己二烯）存在下，反应产率相近。这些结果表明，环芳构化反应是通过离子环化途径进行的，而不是通过双自由基中间体进行的，为了阻止环化反应中的离子途径，合成了具有吸电子基团的分子，使阳离子碳中心不稳定。这些化合物在酸性介质中的反应主要或专门通过双自由基中间体产生产物。其中一些表现出相对较强的DNA损伤活性。对这类化合物的类似物的研究和具有生物活性的烯二炔的开发仍在继续。