Novel Approaches for Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

• 批准号: 8135195
• 负责人: BARRY M TROST
• 金额: $ 41.91万
• 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/8135195
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Inventing new drugs for the treatment of cancer and viruses requires a better understanding of mechanisms and the relation of structure to function. This proposal helps to address this key challenge by developing the underlying initial technology within classes of compounds having demonstrably antitumor or antiviral activities.

描述（由申请人提供）：抗肿瘤和抗病毒药物的治疗重要性需要持续努力开发新的方法来定义显着改进的有效合成策略，以更好地理解结构-生物活性关系。选择具有这种生物活性的化合物作为目标，该项目开发了新的化学原理，这些原理可能演变成创造这种分子结构的前所未有的策略。为了提高选择性和原子经济性，目前正在研究的四种化学反应是实现这些目标的新核心技术——不对称烯丙基烷基化反应、形成奇数元环的环加成反应、前所未有的通过简单加成形成C-C键的反应，以及自发自组装双核金属配合物进行不对称催化的能力。通过研究钯和钼催化的不对称烯丙基烷基化的新亲核试剂，大大简化了以communesin、gliocladins/ lepptosins和重氮酰胺为代表的吲哚类生物碱以及以vindoline和kopimaline A为代表的iboga型生物碱。对前所未有的[6+3]不对称环加成的前景进行了研究，提供了一种新的解决多药耐药问题的氧吲哚生物碱。大环内酯具有高度多样化的结构类型，作为抗癌和抗病毒药物具有强大而多样的活性。非常有效的月桂醛和两萜内酯，其结构有待证实，代表了结构类型探索新的方向，钌催化的C-C键的形成。Peluroside A是一种高度活跃的细胞凋亡诱导剂，以apicularin A为代表的水杨酸酯内酯激发了双核金属配合物在不对称催化中的多种新应用。以强效细胞因子诱导剂leustroducsin B为代表的具有多种活性的密集功能化的光动素可能简化为一种高度收敛的策略，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。公共卫生相关性：发明治疗癌症和病毒的新药需要更好地了解机制和结构与功能的关系。该提案通过开发具有明显抗肿瘤或抗病毒活性的化合物类别的潜在初始技术，有助于解决这一关键挑战。