SYNTHETIC STUDIES RELATED TO CANCER RESEARCH & TREATMENT

该提案描述了一个全面的计划， 合成、机械、生物和计算机模拟研究 目的在于阐明所证明的作用方式， 潜在的癌症化疗药物，在合理的设计， 和发展的新类别的抗肿瘤剂，并在 制定新的方法和战略， 合成这些试剂。 五个项目建议 调查 一项主要的继续研究将针对 新抑癌素发色团，最近发现的，结构 新制癌素（NCS）的前所未有的生物活性亚基， 一种用于人类癌症化疗的药物 努力将重点放在如下 确定NCS抗肿瘤活性的分子基础， 建立其DNA切割选择性的基础， 利用这些信息进行合理的设计， 抗肿瘤剂，以及简化的类似物的合成， 这些研究所需的生物探针。 第二主 该项目的重点是dynemicin A（Dyn A），一个令人兴奋的新 在体外和体内表现出显著的化疗先导物 抗肿瘤活性。 注意力将集中在 Dyn A的活化，在新Dyn的合理设计和开发 A类似物，在其DNA损伤选择性的结构基础上， 并在审查一个潜在的仿生方法， 前所未有的结构。 第三个项目是针对 开发全新类型的DNA裂解剂， 潜在的癌症化学治疗剂，其被设计为通过以下方式起作用： 过渡金属、光化学和扭转诱导 双自由基形成 第四项主要工作集中在紫杉醇上， 化合物，其最近令人印象深刻的临床表现可能会 导致其即将被批准用于癌症化疗。 这 这项研究的目的是开发紫杉醇的实用方法 类似物，并阐明了结构要求， 紫杉醇的活性。 最后一个项目需要完成以下研究： 合成阿氏毒素。 总的来说，这项研究计划是 预计在化学，生物学和生物学方面具有重要价值， 药

This proposal describes a comprehensive program involving synthetic, mechanistic, biological, and computer modeling studies directed at the elucidation of the mode of action of demonstrated and of potential cancer chemotherapeutic agents, at the rational design and development of new classes of antitumor agents, and at the development of fundamentally new methodology and strategies for the synthesis of such agents. Five projects are proposed for investigation. A major continuation study will be directed at neocarzinostatin chromophore, the recently identified, structurally unprecedented, biologically active subunit of neocarzinostatin (NCS), a drug used in human cancer chemotherapy. Efforts will focus on determining the molecular basis for the antitumor activity of NCS, on establishing the basis for its DNA cleavage selectivity, on the utilization of this information in the rational design of new antitumor agents, and on the synthesis of simplified analogues and biological probes needed in support of these studies. A second major project is focussed on dynemicin A (Dyn A), an exciting new chemotherapeutic lead exhibiting significant in vitro and in vivo antitumor activity. Attention will be directed at the mechanism of activation of Dyn A, at the rational design and development of new Dyn A analogues, at the structural basis for its DNA lesion selectivity, and at an examination of a potentially biomimetic approach to its unprecedented structure. A third project is directed at the development of fundamentally new classes of DNA-cleaving agents and potential cancer chemotherapeutics that are designed to function by the transition metal, photochemical, and torsional induction of diradical formation. A fourth major effort is focussed on taxol, a compound whose recent, impressive clinical performance is likely to result in its imminent approval for use in cancer chemotherapy. This study is directed at the development of practical approaches to taxol analogues and at the elucidation of the structural requirements for taxol's activity. A final project entails completion of studies on the synthesis of aplysiatoxin. Overall, this research program is expected to be of significant value in chemistry, biology, and medicine.