Synthesis and Chemical Biology of Oxazolidinone and Pyrrolidine Natural Products

恶唑烷酮和吡咯烷天然产物的合成及化学生物学

• 批准号: 9319265
• 负责人: Joshua G. Pierce
• 金额: $ 26.84万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319265
• 关键词: Acids; Acylation; Alkaloids; Amino Acids; Antibiotics; Area; Attention; Bacteria; Bacterial Infections; Biological; Biological Assay; Biology; Breathing; Cell Proliferation; Chemicals; Chemistry; Claisen rearrangement; Clinic; Common Core; Communities; Cyclization; Data; Development; Evaluation; Family; Family member; Funding; Goals; Hand; Hydroxyl Radical; Imines; Lead; Malignant Neoplasms; Methods; Natural Products; Oxazolidinones; Oxides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Process; Property; Protocols documentation; Public Health; Pyrrolidines; Pyrrolidinones; Reaction; Recording of previous events; Research; Scheme; Series; Source; Structure; Structure-Activity Relationship; Synthesis Chemistry; Therapeutic; Toxic effect; Tumor Cell Line; Variant; Work; analog; antimicrobial; antimicrobial drug; antitumor agent; bacterial resistance; bioactive natural products; cell type; chemical reaction; clinically relevant; cytotoxic; design; enol; human disease; improved; member; method development; natural antimicrobial; novel; novel drug class; organic acid; pretazettine; public health relevance; scaffold; tumor; unnatural amino acids

 DESCRIPTION (provided by applicant): This proposal describes the development of novel chemical reactions for heterocycle synthesis and the application of these reactions to bioactive natural products. Specifically, a one-pot imine acylation/enol cyclization cascade has been developed that can selectively provide 4-oxazolidinones or pyrrolidones in a stereoselective fashion and these reactions have been applied to the total synthesis of the synoxazolidinones and pretazettine. The synoxazolidinones are recently discovered antimicrobial natural products with novel structures and promising activity against several clinically relevant bacterial strains. Pretazettine is an alkaloid bearing a densely functionalized pyrrolidine core and cytotoxic activit against several types of tumors. The objective of the proposed research is to develop a scalable and expedient approach to these two families of bioactive natural products and leverage the synthetic work to develop new chemical probes and lead compounds for antimicrobial and anticancer development. We have already developed a diastereoselective approach to the synoxazolidinones and prepared analogs with activity superior to that of the natural products. We aim to further refine our synthetic approach and apply it to other members of the synoxazolidinone family while continuing to optimize the 4-oxazolidinone scaffolds for potency and selectivity towards bacteria. In parallel to these efforts we have expanded the scope of our reaction to provide pyrrolidone derivatives, which are broadly useful building blocks in medicinal chemistry and natural product synthesis. Utilizing this approach we propose an extremely rapid preparation of pretazettine, an alkaloid that has received significant attention from the synthetic community. We expect that our synthetic work will provide new reactions to construct heterocycles of broad utility and lead to approaches to natural products that enable their use as chemical probes. These synthetic studies are complimented by chemical biology studies to explore the activity of both natural products and analogs against clinically relevant bacteria and tumor cell lines. Taken together, these efforts will provide a framework for the development of new synthetic chemistry and potential lead compounds for the treatment of bacterial infections and cancer.

 描述（由申请人提供）：该提案描述了用于杂环合成的新型化学反应的开发以及这些反应在生物活性天然产物中的应用。具体来说，已经开发了一种一锅亚胺酰化/烯醇环化级联，可以选择性地提供4。以立体选择性方式合成恶唑烷酮或吡咯烷酮，这些反应已应用于合成恶唑烷酮和 pretazettine 的全合成。 Synoxazolidinones 是最近发现的抗菌天然产物，具有新颖的结构和对几种临床相关细菌菌株的良好活性。 Pretazettine 是一种生物碱，具有密集功能化的吡咯烷核心，具有针对多种类型肿瘤的细胞毒性活性。本次研究的目的是针对这两个生物活性天然产物家族开发一种可扩展且便捷的方法，并利用合成工作来开发新的化学品。我们已经开发了一种针对 Synoxazolidinones 的非对映选择性方法，并制备了活性优于该方法的类似物。我们的目标是进一步完善我们的合成方法并将其应用于 Synoxazolidinone 家族的其他成员，同时继续优化 4-恶唑烷酮支架的效力和对细菌的选择性。我们的反应提供了吡咯烷酮衍生物，这些衍生物是药物化学和天然产物合成中广泛使用的基础材料，我们提出了一种极其快速的 Pretazettine 制备方法，这是一种已收到的生物碱。受到合成材料的极大关注 我们期望我们的合成工作将提供新的反应来构建具有广泛用途的杂环，并找到能够将其用作化学探针的天然产物的方法，这些合成研究得到化学生物学研究的补充，以探索这两种天然产物的活性。总而言之，这些努力将为开发用于治疗细菌感染和癌症的新合成化学和潜在先导化合物提供框架。