SYNTHESIS OF BIOACTIVE COMPLEX ALKALOIDS

生物活性复合生物碱的合成

• 批准号: 7682938
• 负责人: David Y Gin
• 金额: $ 38.74万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-10 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682938
• 关键词: Acute; Address; Alder plant; Alkaloids; Antifungal Agents; Antiviral Agents; Architecture; Area; Binding; Biological; Biological Factors; Cancer cell line; Carbodiimides; Cells; Colon Carcinoma; Complex; Cyclopentane; Cytotoxic Antibiotics; Cytotoxin; DNA Sequence Rearrangement; Development; Dissociation; Evaluation; Exhibits; Family; Family member; Foundations; Generations; Goals; Guanidines; HIV; HIV Envelope Protein gp120; Health; Human; Human Biology; Imidates; Imidazole; Imines; Immunosuppressive Agents; Inhibitory Concentration 50; Investigation; Ion Channel; Lethal Dose 50; Malignant Epithelial Cell; Medicine; Methods; Mus; Nitrogen; Organic Chemistry; Palau' amine; Principal Investigator; Process; Protein Tyrosine Kinase; Pyrimidine; Pyrimidines; Pyrroles; Reaction; Research; Therapeutic; Therapeutic Agents; Toxic effect; abstracting; chemical synthesis; crambescidin 816; cycloaddition; cylindrospermopsin; cytotoxic; cytotoxicity; guanidinium; immunoregulation; innovation; interest; ion channel blocker; leukemia; marine natural product; member; novel; programs; response; small molecule

ABSTRACT This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex alkaloid natural products. Within each total synthesis goal lies the implicit aim of discovering and exploiting new reactions that push the boundaries of chemical synthesis innovation. In this context, new strategies for the total synthesis of several guanidine-containing complex alkaloids will be explored. These classes of targets include the family of anti-HIV/immunomodulating batzelladine alkaloids, the family of anticancer and ion-channel disrupting crambescidin alkaloids, the potent cytotoxin cylindrospermopsin, and the powerful immunosuppressant palau'amine. All of these natural products exhibit significant yet distinct biological responses, yet they are all structurally characterized by at least one guanidine moiety embedded within a complex polycyclic architecture, a synthetic challenge that will be addressed by investigating novel annulation strategies and reactions for nitrogen-heterocycle synthesis. These proposed goals will involve investigation diastereoselective [4+2]-annulation of vinyl carbodiimides with chiral imine and imidate derivatives for dihydropyrimidine and pyrimidine synthesis, as well as other convergent cycloaddition strategies for the construction of fully substituted all-cis cyclopentanes. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex alkaloid synthesis, but also provide access to complex natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function. PROJECT NARRATIVE This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex guanidine alkaloid natural products. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex molecule synthesis, but also provide access to natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function.

抽象的 该研究计划的重点是开发新的合成策略，以全面合成 生物活性复杂的生物碱天然产物。在每个整体综合目标中，目标都在于 发现和利用新反应，以推动化学合成创新的边界。在这个 上下文，几种含鸟嘌呤复合物生物碱的总合成的新策略将是 探索。这些类别的目标包括抗HIV/免疫调节的batzelladine生物碱的家族， 抗癌和离子通道家族破坏了crambescidin生物碱，有效的细胞毒素 圆柱植物和强大的免疫抑制剂palau'amine。所有这些天然产品展出 显着但鲜明的生物学反应，但它们在结构上都以至少一个鸟根为特征 嵌入复杂多环体结构中的部分是一个合成的挑战 研究氮杂环合成的新型环形策略和反应。这些提议 目标将涉及调查映选择性[4+2] - 用手性亚胺和 对二氢吡啶胺和嘧啶合成的衍生物以及其他收敛性环加成 建造完全取代的全CIS环戊植物的策略。这些目标成功合成 分子不仅将为复杂的生物碱合成奠定高效且实用的策略的基础，还将为 还可以访问各种生物学兴趣和治疗潜力的复杂天然产品 卫生区域，包括小分子细胞毒/抗癌，抗病毒和免疫调节剂 作为独特的杂环构造，这些构造专门破坏了离子通道函数。项目叙述 该研究计划的重点是开发新的合成策略，以全面合成 生物活性复杂的鸟嘌呤生物碱天然产物。这些靶分子成功合成 不仅将为复杂分子综合的高效和实用策略奠定基础，还将为 提供在各种卫生领域的生物学兴趣和治疗潜力的天然产品， 包括小分子细胞毒性/抗癌，抗病毒和免疫调节剂，以及独特的 杂环构造特别破坏离子通道函数。