Novel Approaches for Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

• 批准号: 8318840
• 负责人: BARRY M TROST
• 金额: $ 42.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318840
• 关键词: 3-hydroxybutanal; Acquired Immunodeficiency Syndrome; Address; Aldehydes; Alkaloids; Alkenes; Alkylation; Alkynes; Antiviral Agents; Apoptosis; Apoptosis Promoter; Architecture; Area; Attention; Behavior; Biological; Blood Cells; Budgets; Carbon; Carboxylic Acids; Catalysis; Chemicals; Chemistry; Complex; Coupling; Cyanobacterium; Development; Education; Effectiveness; Event; Face; Family; Generations; Glycols; Goals; Grant; Growth; Human Resources; Iboga; Immunocompromised Host; Investigation; Isothiocyanates; Ketones; Knowledge; Laboratories; Lactones; Lead; Left; Ligands; Malignant Neoplasms; Metals; Methodology; Methods; Microtubules; Mitomycins; Modification; Molecular; Molybdenum; Multi-Drug Resistance; Nature; Nitrogen; Oxidation-Reduction; Palladium; Pharmaceutical Preparations; Process; Production; Progress Reports; Pyrans; Reaction; Reagent; Reporting; Research; Route; Ruthenium; Solutions; Structure; Students; System; Technology; Testing; Time; Translating; Verapamil; Vindoline; Virus; Work; amphidinolide A; amphidinolide B; antiangiogenesis therapy; antitumor agent; base; cancer therapy; catalyst; chemical reaction; chemotherapy; compare effectiveness; cycloaddition; cytokine; cytotoxic; design; frontier; improved; indoline; insight; laulimalide; leustroducsin B; member; metal complex; novel; novel strategies; oxindole; propadiene; propargyl alcohol; salicylate; stereochemistry; tetrahydrofuran

Project Summary. The thereapeutic importance of antitumor and antiviral agents requires a continued effort to develop new methodology to define significantly improved efficient synthetic strategies to better understand structure - biological activity relationships. Choosing classes of compounds known for this type of biological acitivity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Four general types of chemical reactions under investigation to improve selectivity and atom economy serve as the new core technology to realize these goals - asymmetric allylic alkylation, cycloadditions to form odd membered rings, unprecedented C-C bond forming reactions by simple additions, and the ability to spontaneously self-assemble dinuclear metal complexes for asymmetric catalysis. Indoline alkaloids represented by rather diverse structures such as communesins, gliocladins/leptosins, and diazonamides as well as iboga type alkaloids represented by vindoline and kopimaline A are greatly simplified by examining new classes of nucleophiles for palladium and molybdenum catalyzed asymmetric allylic alkylation. Examination of the prospect of an unprecedented [6+3] asymmetric cycloaddition provides access to a novel oxindole alkaloid that addresses multidrug resistance. Macrocyclic lactones constitute a highly diverse array of structural types possessing potent and diverse activities as anti-cancer and antiviral agents. The very potent laulimalide and the amphidinolides, whose structures need confirmation, represent structural types that probe new directions for ruthenium catalyzed C-C bond formation. Peluroside A, a highly active inducer of apoptosis, and the salicylate macrolactones represented by apicularin A stimulate multiple new applications of asymmetric catalysis using dinuclear metal complexes. The densely functionalized pholactomycins which show diverse activity represented by leustroducsin B, a potent cytokine inducer, may simplify to a highly convergent strategy where its stereochemistry largely derives from both the dinuclear metal complexes and the asymmetric allylic alkylation reaction.

项目摘要。 抗肿瘤和抗病毒药物的治疗重要性要求继续努力开发新的抗肿瘤和抗病毒药物。 定义显著改进的有效合成策略以更好地理解结构的方法学- 生物活性关系。选择已知具有此类生物活性的化合物类别， 目标，该项目开发新的化学原理，可能演变成前所未有的战略， 创造出这样的分子结构。研究中的四种常见化学反应， 选择性和原子经济性是实现这些目标的新的核心技术--不对称烯丙基 烷基化，环加成形成奇数元环，通过简单的C-C键形成反应， 加成，以及自发自组装双核金属配合物用于不对称催化的能力。 吲哚生物碱以相当不同的结构为代表，如communesins，gliocladins/leptosins， 重氮酰胺类以及以文多灵和可匹马林A为代表的iboga型生物碱大大简化， 通过考察钯和钼催化的不对称烯丙基的新型亲核试剂， 烷基化对前所未有的[6+3]不对称环加成反应的前景的研究提供了 一种新的羟吲哚生物碱，解决多药耐药性。大环内酯构成了一种高度 具有作为抗癌剂和抗病毒剂的有效和多种活性的多种结构类型。 非常有效的laulimalide和amphidinolides，其结构需要确认，代表结构 这些类型为钌催化的C-C键形成探索了新的方向。Peluroside A，一种高活性 细胞凋亡诱导剂，以及以apicularin A为代表的水杨酸大环内酯刺激多种新的 双核金属配合物的不对称催化应用。密集功能化的 以亮乳球菌素B（一种有效的细胞因子诱导剂）为代表的表现出不同活性的pholactomycins可 简化为高度收敛的策略，其中其立体化学主要来自双核金属 配合物和不对称烯丙基烷基化反应。