ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS

生物活性生物碱的不对称合成

• 批准号: 3295501
• 负责人: PHILIP P GARNER
• 金额: $ 10.76万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3295501
• 关键词: alkaloids; antineoplastics; chemical structure function; deoxycytidine; drug design /synthesis /production; isoquinolines; photochemistry; stereochemistry; ylide

The objective of this proposal is to develop a new synthetic approach to the naphthyridinomycin and quinocarcin families of isoquinoline alkaloids. Since these substances inhibit DNA synthesis they are potential antineoplastic agents. Methodology will be explored that allows for the stereoselective assembly of these structurally complex targets from chiral, nonracemic precursors. Thus asymmetric syntheses of the requisite phenylglycinol derivatives will be investigated first. These starting materials will be incorporated into a scheme that relies on a novel 1,3-dipolar cycloaddition reaction to construct the 3,8- diazabicyclo(3.2.1)octane moiety common to both target families. In this context, complimentary photochemical and thermal routes to azomethine ylides will be explored. The latter method would involve a novel valence tautomerization of enamines for ylide generation. Both inter- and intramolecular variations of this key addition will be investigated in detail, with complete stereocontrol as a goal. Subsequent Hoesch cyclization (isoquinoline formation) sets the stage for the final sequence of events that should lead to the desired targets and analogues thereof. As mentioned above, these target substances have been shown to inhibit DNA synthesis and (at least for naphthyridinomycin) this seems to occur as a result of irreversible binding to the deoxyguanidylic acid - deoxycytidylic acid base pairs. A logical extension of the proposed synthetic work would be an investigation into the exact nature of this binding to DNA and the chemical events (ie. activation of the antibiotic) that precede it. Such studies would be useful for the rational design of new antineoplastic agents with minimal unwanted side effects. More importantly perhaps, work of this nature could lead to a better understanding (and thus control) of DNA synthesis at the cellular level and the medical problems associated with the malfunction of this process.

该提案的目的是开发一种新的合成 对萘啶霉素和奎奴卡辛家族的研究 异喹啉生物碱。 由于这些物质抑制DNA 合成它们是潜在的抑制剂。 方法 将探索允许立体选择性组装 这些结构复杂的目标来自手性、非外消旋 前体 因此，不对称合成所需的 首先研究苯基甘氨醇衍生物。 这些 起始材料将被纳入一个依赖于 研究了一种新的1，3-偶极环加成反应，以构建3，8- 二氮杂双环（3.2.1）辛烷部分是两个靶家族共有的。 在这种情况下，互补的光化学和热路线 甲亚胺叶立德将进行探索。 后一种方法将 涉及烯胺形成叶立德新的价态互变异构 一代 这一关键的分子间和分子内变异 此外，将详细调查，并完成 立体控制作为目标。 后续Hoesch环化 （异喹啉形成）为最终序列奠定了基础 这些事件应该导致所需的目标和类似物 它们的 如上所述，这些目标物质已被证明 抑制DNA合成和（至少对于萘啶霉素）这 似乎是由于不可逆转的结合， 脱氧胍酸-脱氧胞苷酸碱基对。 逻辑 延长拟议的综合工作将是一项 研究这种与DNA结合的确切性质， 化学事件（即，抗生素的作用）。 这些研究将有助于合理设计新的 具有最小副作用的药物。 更 也许重要的是，这种性质的工作可以导致更好的 理解（从而控制）细胞内的DNA合成 水平和医疗问题与故障的 这个过程