Development of Anticancer Agents Based on Photochemical DNA-Cleavage

许多非环(Z)-1，2，4-庚三烯-6-YNE经环芳构化反应生成反应性脱氢甲苯双自由基，作为一类有效的抗肿瘤抗生素新卡西宁(NCS)的化学模型进行了研究。制备具有引发脱氢甲苯双自由基生成的特征触发装置的烯炔-丙二烯模型是当前的一个具有挑战性的问题。为了开发这类分子，我们设计了各种模型，通过Myers-Saito环化生成碳双自由基。例如，我们在酸性介质中合成了具有α-羟基结构的萘酸酯类化合物，并展示了在酸性介质中双自由基的形成反应，为了阐明这些级联反应的机理和开发生物活性物质，制备在温和条件下进行环芳化反应的热稳定性羧酸衍生物是必不可少的。为此，我们设计了新型的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。在甲醇中的反应速度相对较慢，在无自由基清除剂(O2或1，4-环己二烯)存在或无自由基清除剂的情况下，分别以相似的产率生成产物。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。为了防止环化反应中的离子途径，合成了具有不稳定阳离子碳中心的吸电子基团的分子。这些化合物在酸性介质中的反应主要或完全通过双自由基中间体产生产物。其中一些化合物表现出相对较强的DNA损伤活性。对这类化合物的类似物的研究和生物活性烯二炔的开发仍在继续。

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.