TOTAL SYNTHESIS OF MYCOTOXINS AND RELATED COMPOUNDS

霉菌毒素及相关化合物的全合成

• 批准号: 3072969
• 负责人: JIN K CHA
• 金额: $ 6.44万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-28 至 1995-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3072969
• 关键词: DNA; O glycosidase; adenylate cyclase; allyl compound; antineoplastics; antiviral agents; cardiac glycoside aglycone; chemical carcinogen; circular dichroism; drug design /synthesis /production; enzyme inhibitors; erythromycin; forskolin; ion transport; mycotoxins; nuclear magnetic resonance spectroscopy; nucleic acid structure; oxidative phosphorylation; oxygen; polyenes; prostaglandins

The proposed program is directed at the development of new synthetic methods and the total synthesis of biologically active natural products. An area of particular interest involves the stereo-control of prochiral sp2 sites by an allylic oxygen substituent, and its application to the total synthesis of a wide range of multifunctional natural products and their various synthetic derivatives in significant quantities for biological testing. Specific target molecules include: polyhydroxy indolizidine alkaloids, which act as potent glycosidase inhibitors; several Dendrobatid alkaloids, which provide invaluable tools for the investigation of ion transport in many biological systems; polyene mycotoxins of the citreoviridin family, which are potent inhibitors of oxidative phosphorylation; forskolin, which has been shown to activate adenylate cyclase and display a wide range of physiological effects; the seco acid of erythronolide A, the aglycon of erythromycin A, which is undoubtedly one of the most active and important macrolide antibiotics; and prostanoids, the biogenesis of which has fascinating evolutionary implications. We hope that our synthetic studies eventually would lead to mechanistic insights helpful in designing and rationalizing new stereoselective reactions. Ongoing and planned collaborations with other laboratories include investigations: to gain an understanding of the relationship between the structures of known carcinogens (such as polycyclic aromatic hydrocarbons) and their ability to modify the DNA structure, to induce mutations and to cause cancer, to determine structure and conformation of the adducted oligomers by high field NMR, circular dichroism and other biophysical techniques; to search for azasugars of therapeutic potential as antiviral and anticancer agents and for rational design and synthesis of reversible and irreversible alkaloidal glycosidase inhibitors, which should be useful in examining biological specificity at the cell surface; to elucidate biogenesis of prostanoids such as PGA2 and clavulone, which are produced in primitive marine organisms; and to determine biosynthetic pathways of polyene pyrone mycotoxins.

拟议的计划旨在开发新的合成材料 具有生物活性的天然产物的方法和全合成。 特别感兴趣的领域涉及前手性 sp2 的立体控制 烯丙基氧取代基的位点及其在总 多种多功能天然产物的合成及其 大量用于生物的各种合成衍生物 测试。 具体靶分子包括：多羟基吲哚里西啶 生物碱，作为有效的糖苷酶抑制剂；几只石杷虫 生物碱，为研究离子提供了宝贵的工具 许多生物系统中的运输；多烯真菌毒素 黄绿绿素家族，是氧化酶的有效抑制剂 磷酸化；毛喉素，已被证明可以激活腺苷酸 环化酶并表现出广泛的生理效应；断链酸 erythronolide A，红霉素A的苷元，无疑是其中之一 最活跃和最重要的大环内酯类抗生素；和前列腺素， 其生物起源具有令人着迷的进化意义。 我们希望 我们的综合研究最终将带来机械见解 有助于设计和合理化新的立体选择性反应。 与其他实验室正在进行和计划的合作包括 调查：了解事物之间的关系 已知致癌物（如多环芳烃）的结构 以及它们修改 DNA 结构、诱导突变和 导致癌症，确定加合体的结构和构象 低聚物的高场核磁共振、圆二色性和其他生物物理 技术；寻找具有抗病毒治疗潜力的氮杂糖 和抗癌剂以及合理设计和合成可逆的 和不可逆的生物碱糖苷酶抑制剂，应该有用 检查细胞表面的生物特异性；阐明 前列腺素类化合物（例如 PGA2 和克拉维酮）的生物发生，这些物质产生于 原始海洋生物；并确定生物合成途径 多烯吡喃酮霉菌毒素。