SYNTHETIC STUDIES RELATED TO CANCER RESEARCH & TREATMENT

这份提案描述了一项全面的计划，包括 综合、机械、生物和计算机模拟研究 旨在阐明被证明的和被证明的 潜在癌症化疗药物的合理设计 以及新型抗肿瘤药物的开发，并在 制定全新的方法和战略 这类试剂的合成。提出了五个项目， 调查。一项主要的继续研究将针对 新卡津抑素发色团，结构上的新发现 史无前例的，具有生物活性的新卡西诺抑素(NCS)亚单位， 一种用于人类癌症化疗的药物。努力的重点将放在 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，基于 这些信息在新建筑合理设计中的应用 抗肿瘤药物，以及简化类似物和 支持这些研究所需的生物探针。第二个大调 该项目的重点是动力米星A(Dyn A)，一种令人兴奋的新 化学治疗铅在体外和体内均有显著意义 抗肿瘤活性。我们将把注意力集中在 在合理设计和开发新的Dyn时激活Dyn A A类似物，在其DNA损伤选择性的结构基础上， 在一次对其潜在仿生方法的研究中 史无前例的结构。第三个项目是针对 开发全新类别的DNA裂解剂和 潜在的癌症化疗药物，旨在通过 过渡金属、光化学和扭转诱导 双基形成。第四个主要努力集中在紫杉醇上，一种 其近期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 研究的目标是开发紫杉醇的实用方法 类似物，并在阐明结构要求时 紫杉醇的活性。最后一个项目需要完成关于 鱼腥藻毒素的合成。总体而言，这个研究计划是 有望在化学、生物和生物领域具有重要价值 医药。

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.