Diverse-Target Synthesis: Direct Access to the Bioactive Xenicane Family Tree

多靶点合成：直接获取生物活性 Xenicane 家族树

• 批准号: 7569382
• 负责人: Stephen Dominic Lotesta
• 金额: $ 4.07万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569382
• 关键词: Acids; Alder plant; Alkenes; Anti-Bacterial Agents; Bacterial Infections; Biological; Biological Factors; Biology; CDK6-associated protein p18; Cancer Biology; Cyclization; Diels Alder reaction; Disease; Epoxy Compounds; Evaluation; Genealogical Tree; Goals; Kinetics; Mediating; Methods; Modality; Modern Medicine; Organism; Pharmaceutical Preparations; Public Health; Research; Research Proposals; Resolution; Route; Scheme; System; Titanium; Trees; chemical synthesis; drug development; small molecule; titanocene; tool

DESCRIPTION (provided by applicant): The goal of this research proposal is to synthesize the biologically active xenicane small molecule natural products in order to facilitate further research to understand the biology of cancer and bacterial diseases. A significant number of anticancer and antibacterial drugs have been developed over the past twenty years primarily due to the studies of small molecule natural products (SMNPs). Owing to the paucity of material from non-renewable, slow-growing organisms the total chemical synthesis of SMNPs is required for rigorous biological evaluation. A short and concise synthetic route to a suite of structurally diverse and biologically active SMNPs would provide material for research to help understand the biology of diseases and determine new modalities for disease treatment. In this proposal a strategy that incorporates both a target- and diversity-oriented approach will be used to gain direct access to the semi-validated anticancer and antibacterial xenicane family tree of SMNPs. Key steps in this synthesis include Oppolzer hydroboration/transmetallation cyclization, dynamic kinetic resolution using the Shi epoxidation, Diels- Alder/retro Diels-Alder reaction, and titanium radical and Lewis acid mediated transannulations. Relevance of proposed research to public health: The biology of cancer and bacterial diseases is not yet fully understood. The synthesis and evaluation of new biologically active compounds is needed for drug development and determination of new methods for disease treatment. The synthetic route in this proposal would give access to a suite of bioactive natural products which can serve as tools to facilitate further research to understand the biology of cancer and bacterial diseases in an effort to advance modern medicine.

描述（由申请人提供）：本研究计划的目标是合成具有生物活性的xenicane小分子天然产物，以促进进一步研究，了解癌症和细菌性疾病的生物学。在过去的二十年中，主要由于对小分子天然产物（SMNP）的研究，已经开发了大量的抗癌和抗菌药物。由于缺乏来自不可再生、生长缓慢的生物体的材料，需要SMNP的全化学合成进行严格的生物学评价。一个简短而简洁的合成路线，一套结构多样的和生物活性的SMNP将提供材料的研究，以帮助了解疾病的生物学和确定新的疾病治疗方式。在本提案中，将采用一种结合靶向和多样性导向方法的策略，以直接获得SMNP的半验证抗癌和抗菌xenicane家族树。该合成的关键步骤包括Oppolzer硼氢化/transmethalo环化、Shi环氧化动力学拆分、Diels-桤木/retro Diels-桤木反应、钛自由基和刘易斯酸介导的transannulations。拟议研究与公共卫生的相关性：癌症和细菌性疾病的生物学尚未完全了解。新的生物活性化合物的合成和评价是药物开发和确定疾病治疗新方法所必需的。该提案中的合成路线将提供一系列生物活性天然产品，这些产品可以作为促进进一步研究的工具，以了解癌症和细菌疾病的生物学，从而推动现代医学的发展。