ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS

生物活性生物碱的不对称合成

• 批准号: 3295495
• 负责人: PHILIP P GARNER
• 金额: $ 10.11万
• 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/3295495
• 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.

这项提议的目标是开发一种新的合成材料 赤霉素类和环胞菌素家族的初步研究 异喹啉生物碱。因为这些物质会抑制DNA 合成：它们是潜在的抗肿瘤药物。方法论 将探索允许立体选择性组装的 这些来自手性、非外消旋的结构复杂的靶标 先驱物。因此，必要的不对称合成 首先将研究苯甘氨酚的衍生物。这些 起始材料将被纳入一个依赖于 一种新的1，3-偶极环加成反应合成3，8- 二氮杂双环(3.2.1)辛烷部分为两个目标家族所共有。 在这方面，免费的光化学和热能途径 到甲亚胺的叶立德将被探索。后一种方法将 涉及叶立德中烯胺的一种新的价式互变异构化 一代。该密钥的分子间和分子内变异 将对添加进行详细调查，并完成 以立体控制为目标。随后的Hoesch环化反应 (异喹啉形成)为最终序列奠定了基础 应导致预期目标和类似物的事件 其中之一。 如上所述，这些目标物质已被证明 抑制DNA合成和(至少对萘霉素)这一点 似乎是由于不可逆地绑定到 脱氧鸟苷酸-脱氧胞苷酸碱基对。一个合乎逻辑的 拟议的合成工作的延长将是一个 对这种与DNA的结合的确切性质以及 化学事件(即抗生素的激活)。 这些研究将有助于新建筑的合理设计。 副作用最小的抗肿瘤药物。更多 也许重要的是，这种性质的工作可以带来更好的 在细胞内理解(并因此控制)DNA合成 水平和与故障相关的医疗问题 这一过程。