SYNTHETIC/MECHANISTIC INVESTIGATIONS OF ANTITUMOR AGENTS

安古环素类化合物的合成和机理研究 抗肿瘤药物是这项提案的目标之一。一种高效的 对安古环素家族几个成员的对映体选择性策略 概述了抗肿瘤抗生素的研究现状。总体战略的关键是 四环系统的对映选择性组装体，包括 抗生素的苷元部分通过Diels-Alder环加成反应。这个 Diels-Alder反应的二烯组分在 从(-)-奎尼酸开始的光学活性形式。紧随其后的是 环系统的构建，新的途径 描述了关键氧官能团的立体控制引入。 接下来，L-红景天糖的合成 概述了许多环素类抗生素的低聚糖部门。 低聚糖及其立体控制组装的方法学 抗肿瘤抗生素长春霉素B2的合成应用 并对PI-080进行了描述。胸腺苷的一种收敛合成方法 并对合成酶抑制剂BE-7585A进行了概述。最后，实验 旨在探索空气的潜在关系 抗生素阿卡霉素的二氢对苯二酚式氧化为其 并对其抗肿瘤活性进行了讨论。 这项建议的第二个主要目标是完全合成FR- 66979，一种诱导脱氧核糖核酸-脱氧核糖核酸交联的抗癌剂 进行I期临床试验。成功的关键是 这种抗肿瘤药物的对映选择性合成是金属催化的。 不对称碳氢插入反应生成氮气 含有杂环的。据报道，DNA-DNA交联链的形成 通过一种类似有丝分裂油的中间体。一种综合的方法来解决 描述了可能的烷基化物种的生成。最后， 旨在探索这种中间体的反应性的实验 并对其进行了讨论。 最终，这些调查将导致新的 综合方法学及临床应用 抗癌药物的发展。

Synthetic and mechanistic investigations of the angucycline class of antitumor agents is one objective of this proposal. An efficient enantioselective strategy to several members of the angucycline family of antitumor antibiotics is outlined. Key to the general strategy is the enantioselective assembly of the tetracyclic ring system comprising the aglycone portion of the antibiotics via a Diels-Alder cycloaddition. The diene component of the Diels-Alder reaction is efficiently prepared in optically active form starting from (-)-quinic acid. Following the construction of the ring system, novel approaches for the stereocontrolled introduction of key oxygen functionality are described. Next the synthesis of L-rhodinose a monosaccharide common to the oligosaccharide sector of many angucycline antibiotics is outlined. Methodology for the stereocontrolled assembly of oligosaccharides and its application to the synthesis of the antitumor antibiotics vineomycin B2 and PI-080 is then described. A convergent synthesis of the thymidylate synthase inhibitor BE-7585A is also outlined. Finally, experiments directed towards exploring the potential relationship of the air oxidation of the dihydroquinone form of the antibiotic aquayamycin to its antitumor activity are also discussed. The second major objective of this proposal is the total synthesis of FR- 66979, an anticancer agent which induces DNA-DNA cross-links and has undergone phase I clinical trials. Central to the success of the enantioselective synthesis of this antitumor agent is a metal-catalyzed asymmetric carbon-hydrogen insertion reaction to produce a nitrogen containing heterocycle. DNA-DNA cross-link formation reportedly occurs via a mitosene-like intermediate. A synthetic approach towards the generation of the putative alkylating species is described. Finally, experiments directed towards probing the reactivity of this intermediate is also discussed. Ultimately these investigations will lead to the development of new synthetic methodologies as well as clinical application in the development of anticancer agents.