Novel Approaches for Antitumor and Antiviral Agents

说明(申请人提供)：抗肿瘤和抗病毒药物的治疗重要性需要继续努力开发新的方法学，以确定显著改进的有效合成策略，以更好地了解结构-生物活性关系。选择以这种生物活性著称的一类化合物作为目标，该项目开发了新的化学原理，这些原理可能演变为创建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，正在研究的四类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、形成奇数环的环加成反应、通过简单加成形成前所未有的C-C键反应，以及用于不对称催化的自发自组装双核金属络合物的能力。通过研究新型亲核试剂在钯和钼催化的不对称烯丙基烷基化反应中的作用，可以极大地简化以公社素类、醇类/瘦素类和重氮酰胺类化合物为代表的吲哚类生物碱，以及以长春花碱和可匹马林A为代表的IBOGA类生物碱。对史无前例的[6+3]不对称环加成反应前景的研究提供了一种解决多药耐药的新型氧化吲哚生物碱的途径。大环内酯类化合物构成了一系列高度多样化的结构类型，具有强大而多样的抗癌和抗病毒活性。非常有效的劳利马德和苯并烷内酯的结构需要确认，它们代表了探索Ru催化的C-C键形成的新方向的结构类型。高效的细胞凋亡诱导剂Peluroside A和以杏仁苷A为代表的水杨酸大内酯类化合物激发了双核金属络合物在不对称催化中的多种新应用。白藜芦素B是一种高效的细胞因子诱导剂，它所表现出的不同活性的密集官能化的磷脂酰菌素可以简化为高度收敛的策略，其立体化学主要来源于双核金属络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。这项提议通过在具有明显抗肿瘤或抗病毒活性的化合物类中开发基本的初始技术，帮助解决这一关键挑战。

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.