Novel Approaches for Antitumor and Antiviral Agents

描述（由申请人提供）：抗肿瘤和抗病毒剂的治疗重要性要求持续努力开发新的方法来定义显著改进的有效合成策略，以更好地理解结构-生物活性关系。该项目选择了以这种生物活性而闻名的化合物作为目标，开发了新的化学原理，这些原理可能会演变成创造这种分子结构的前所未有的策略。四个一般类型的化学反应正在调查，以提高选择性和原子经济性作为新的核心技术，以实现这些目标-不对称烯丙基烷基化，环加成形成奇数元环，前所未有的C-C键形成反应，通过简单的添加，并自发自组装双核金属配合物的能力，不对称催化。吲哚生物碱的代表，而不同的结构，如communesins，gliocladins/leptosins，和diazonamides以及iboga型生物碱的vindoline和kopimaline A的代表，大大简化了检查新的类的钯和钼催化的不对称烯丙基烷基化的亲核试剂。一个前所未有的[6+3]不对称环加成的前景检查提供了一个新的羟吲哚生物碱，解决多药耐药性的访问。大环内酯构成了一系列高度多样化的结构类型，具有作为抗癌剂和抗病毒剂的有效和多样化的活性。非常有效的laulimalide和ampdinolides，其结构需要确认，代表的结构类型，探测钌催化的C-C键形成的新方向。Peluroside A是一种高活性的细胞凋亡诱导剂，以apicularin A为代表的水杨酸大环内酯刺激了双核金属配合物不对称催化的多种新应用。以Leustroducsin B（一种有效的细胞因子诱导剂）为代表的密集功能化的pholactomycins显示出不同的活性，可以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理解机制和结构与功能的关系。该提案有助于通过在具有明显抗肿瘤或抗病毒活性的化合物类别内开发基础初始技术来应对这一关键挑战。

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.