HETEROCYCLIC RING COMPOUNDS FOR ALKALOID SYNTHESIS

用于生物碱合成的杂环化合物

• 批准号: 6520026
• 负责人: Albert Padwa
• 金额: $ 23.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520026
• 关键词: DNA damage; alkaloids; antineoplastics; chemical addition; chemical synthesis; drug design /synthesis /production; heterocyclic compounds; ylide

DESCRIPTION: The overall objective of this research program involves the development of general, broadly applicable methods for the synthesis of novel heterocyclic systems. Emphasis is to be placed on the use of 1,3- dipolar cycloaddition chemistry for the construction of a variety of biologically interesting molecules. Among the reactions to be studied are dipolar cycloadditions of carbonyl ylides, azomethine ylides, thiocarbonyl ylides, and mesoionic dipoles. The project will focus on using the rhodium catalyzed reaction of alpha-diazo carbonyl compounds as a method for generating a variety of 1,3-dipoles. It is intended to use the dipolar cycloaddition reaction of a five ring cyclic carbonyl ylide dipole as the key step for the construction of the illudin/ ptaquilosin skeleton. This strategy is to provide for a rapid assembly of the basic core unit of the target molecules having most of the functionality in place. The principal investigator notes that because of their extreme toxicity and consequent low therapeutic index, it seems reasonable to him to modify the basic skeletons so as to reduce cytotoxicity without compromising antitumor activity. His intention is synthesize analogs of these compounds so as to evaluate their DNA cleaving abilities. It is noted that the synthetic analogs may be more stable and more easily available than the natural compounds. The tandem cyclization-cycloaddition chemistry to be developed will also be used for the synthesis of complex alkaloids and to provide quantities of material needed for detailed biological assay. It is reported that many alkaloids have been shown to be carcinogenic and mutagenic and their metabolites are known to react with DNA and other cellular nucleophiles. The principal investigator notes that it should be possible to construct analogs of alkaloids which may be selective enough in their administered form to reach the active sites of tumor cell growth and possess proper alkylating ability to interfere with DNA replication. It is the goal of this proposal to seek support for the preparation of such analogs, which are to be submitted to the NIH for determination of structure activity relationships in the treatment of various cancers. It is stated that the generation of biologically-active compounds by synthesis remains an important part of both health related and chemical research.

描述：本研究计划的总体目标包括 开发通用的、广泛适用的合成方法 新颖的杂环系统。重点是使用 1,3- 用于构建各种偶极环加成化学 生物学上有趣的分子。在待研究的反应中 是羰基叶立德、偶氮甲碱叶立德的偶极环加成， 硫代羰基叶立德和介离子偶极子。该项目将重点关注 利用铑催化的α-重氮羰基化合物的反应 作为产生各种 1,3-偶极子的方法。 其目的是 利用五环环状羰基的偶极环加成反应 叶立德偶极子作为构建隐伞素/的关键步骤 帕奎罗辛骨架。 该策略是为了提供快速组装 目标分子的基本核心单元具有大部分 功能到位。首席研究员指出，因为 其极端毒性和随之而来的低治疗指数，似乎 对他来说合理的修改基本骨架以减少 细胞毒性而不影响抗肿瘤活性。 他的意图是 合成这些化合物的类似物以评估它们的 DNA 劈裂能力。 值得注意的是，合成的类似物可能更 比天然化合物更稳定且更容易获得。 串联 待开发的环化-环加成化学也将用于 复杂生物碱的合成并提供大量材料 需要进行详细的生物学测定。据报道，多种生物碱 已被证明具有致癌性和致突变性及其代谢物 已知可与 DNA 和其他细胞亲核试剂发生反应。 这 首席研究员指出，应该可以构建 生物碱的类似物，其施用可能具有足够的选择性 形成到达肿瘤细胞生长的活性位点并具有适当的 烷化能力干扰 DNA 复制。它的目标是 该提案旨在寻求支持制备此类类似物， 将提交给 NIH 进行结构活性测定 各种癌症治疗中的关系。 据称 通过合成产生生物活性化合物仍然是一个 健康相关研究和化学研究的重要组成部分。