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.

该提议的目的是开发新的合成 萘甲霉素和喹啉霉素的方法 异喹啉生物碱。 由于这些物质抑制了DNA 合成是潜在的抗塑性剂。 方法论 将探索允许立体选择组装的 这些结构上复杂的来自手性，非流行的靶标 前体。 因此必要的不对称合成 苯基乙醇衍生物将首先研究。 这些 起始材料将纳入依赖的计划中 在一种新型的1,3-二极性环加成反应中，以构建3,8-- diazabicyclo（3.2.1）两个目标家族共有的辛烷部分。 在这种情况下，免费的光化学和热路线 将探索偶氮胺的Ylides。 后一种方法将 涉及eNamines ylide的新型价互变异 一代。 该键的分子间和分子内变化 将详细调查添加 立体控制作为目标。 随后的Hoesch环化 （等喹啉的形成）为最终序列设定了阶段 应该导致所需目标和类似物的事件 它。 如上所述，这些目标物质已被证明 抑制DNA合成和（至少对于萘甲霉素） 似乎是由于无法可逆的结合而发生的 脱氧瓜尼酸 - 脱氧胞苷酸碱基对。 逻辑 拟议合成工作的扩展将是 研究这种与DNA和DNA结合的确切性质 化学事件（即抗生素的激活）。 这样的研究对于新的设计很有用 具有最小不良副作用的抗塑料药物。 更多的 也许重要的是，这种性质的工作可能会导致更好 对细胞上DNA合成的理解（并因此控制） 水平和与故障相关的医疗问题 这个过程。