Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的合成

• 批准号: 7529171
• 负责人: EMMANUEL A THEODORAKIS
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529171
• 关键词: Achievement; Alkaloids; Amines; Amino Alcohols; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biological; Biological Factors; Biology; Carbon; Catalysis; Chemical Structure; Chemicals; Chemistry; Class; Collaborations; Complex; Condition; Cyclization; Development; Evaluation; Event; Exhibits; Facility Construction Funding Category; Family; Family member; Furans; Investigation; Knowledge; Laboratories; Lead; Marines; Medicine; Methodology; Methods; Nature; Object Attachment; One-Step dentin bonding system; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Physical condensation; Public Health; Reaction; Research; Science; Stimulus; Structure; System; Testing; Translating; analog; base; bielschowskysin; butenolide; carbonyl group; chemical reaction; chemical synthesis; concept; cycloaddition; design; diene; drug development; furan; interest; marine natural product; member; norcembrenolide; novel; programs; scaffold; sinuleptolide; stem; tool; zoanthenol

DESCRIPTION (provided by applicant): Natural products represent a very significant platform for the development of new drugs and provide a continuous stimulus for research in all areas of science, including chemistry, biology and medicine. The objective of the proposed research is to study methods and develop synthetic strategies that would permit an efficient and stereocontrolled chemical synthesis of representative members from two families of bioactive natural products: the zoanthamine alkaloids and the cembranolides. The targeted natural products have uncommon chemical structures, potent biological activities and unexplored biological modes of action, which attest to their potential as new biological tools and leads for drug development. The proposed methods stem from the unexplored reactivity of electronically rich species, such as dienes and furans, during cycloaddition reactions and highlight the potential of these reactions for the construction of highly functionalized heterocycles. The proposed strategies will test the scope and limitations of the above methods and evaluate their applicability in natural product synthesis. The strategies are also designed to create structural complexity from relatively unfunctionalized starting materials by incorporating multiple carbon-carbon bond forming events in one step. These strategies will pave the way for the synthesis of simplified analogues of the natural products that, in combination with the parent structures, will be used to interrogate the biology of the new chemical structures and translate their chemical reactivity to biological mode of action. PUBLIC HEALTH RELEVANCE: We describe a research program toward the synthesis on two classes of bioactive marine natural products: the zoanthamine alkaloids and the cembranolides. The selected targets have interesting chemical structures and very potent bioactivities as lead structures for the development of new pharmaceuticals. We propose to explore a strategy toward the synthesis of zoanthamines that is inspired by a biosynthesis hypothesis. Our preliminary results suggest that it is possible to synthesize these complex natural products starting from an acyclic precursor by tuning a polycyclization reaction cascade. We plan to explore this reaction cascade for the synthesis of new polycyclic motifs and apply it to the synthesis of zoanthenol. In addition to the synthetic achievements, the results of our study are expected to have great impact in the areas of synthetic methodology, in particular to the reactivity of 2-aminodienes. We also propose to develop a unified approach toward the synthesis of selected cembranolides that is based upon the unexplored reactivity of 1-epoxyfurans. The synthesis of these compounds will pave the way for evaluation of their biological and pharmacological profile that will be pursued in collaboration with experts in the field.

描述(申请人提供)：天然产品代表了新药开发的一个非常重要的平台，并为包括化学、生物和医学在内的所有科学领域的研究提供持续的刺激。拟议研究的目的是研究方法和制定合成战略，使来自两类生物活性天然产物的代表性成员能够进行有效和立体控制的化学合成：黄嘌呤生物碱和西膜内酯。目标天然产物具有不同寻常的化学结构、强大的生物活性和未知的生物作用模式，这证明了它们作为新的生物工具和药物开发的先导的潜力。所提出的方法源于二烯和呋喃等富含电子物种在环加成反应中的未知反应性，并突出了这些反应在构建高官能化杂环方面的潜力。建议的策略将测试上述方法的范围和局限性，并评估它们在天然产物合成中的适用性。这些策略还旨在通过在一个步骤中结合多个碳-碳键形成事件，从相对非功能化的起始材料制造结构复杂性。这些策略将为合成天然产物的简化类似物铺平道路，这些类似物将与母体结构相结合，用于研究新化学结构的生物学，并将其化学反应转化为生物作用模式。 与公共健康相关：我们描述了一项合成两类具有生物活性的海洋天然产物的研究计划：黄嘌呤生物碱和西膜内酯。所选择的目标具有有趣的化学结构和非常强大的生物活性，作为开发新药物的先导结构。我们建议探索一种受到生物合成假说启发的合成偶氮胺的策略。我们的初步结果表明，从无环前体出发，通过调节多环化反应级联反应来合成这些复杂的天然产物是可能的。我们计划探索这一反应级联反应来合成新的多环基序，并将其应用于偶氮菲的合成。除了已有的合成成果外，我们的研究成果有望在合成方法学领域产生重大影响，特别是对2-氨基二烯的反应活性产生重大影响。我们还建议开发一种统一的方法来合成选定的西膜内酯，这是基于1-环氧呋喃的未知反应活性。这些化合物的合成将为评价它们的生物学和药理学特征铺平道路，将与该领域的专家合作开展这项工作。