Ring Expansions to Access Structurally-Diverse Diketopiperazine Alkaloids

环扩展以获得结构多样化的二酮哌嗪生物碱

• 批准号: 9794006
• 负责人: Kyle M. Lambert
• 金额: $ 5.32万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2020-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794006
• 关键词: Academia; Acids; Acute Promyelocytic Leukemia; Address; Adopted; Alkaloids; Amides; Antibiotics; Antiviral Agents; Architecture; Attention; Bacteria; Benign; Biological; Cancer cell line; Cell Line; Cervical; Cervix carcinoma; Chemicals; Complex; Cyclization; Derivation procedure; Development; Digit structure; Dipeptides; Drug Targeting; Exhibits; Family; Foundations; Goals; HL60; Heating; Hela Cells; Human; Hydroxamic Acids; Industry; Libraries; Literature; Malignant Neoplasms; Methodology; Methods; Molecular Conformation; Natural Products; Oxidants; Oximes; Periodicity; Pharmacology; Process; Property; Protocols documentation; Reaction; Reporting; Research; Route; Scientist; Series; Solvents; Source; Structure; Therapeutic; Virus; base; bioactive natural products; cytotoxic; diketopiperazine; drug discovery; fungus; innovation; interest; leukemia; novel; novel therapeutics; scaffold; screening; Academia; Acids; Acute Promyelocytic Leukemia; Address; Adopted; Alkaloids; Amides; Antibiotics; Antiviral Agents; Architecture; Attention; Bacteria; Benign; Biological; Cancer cell line; Cell Line; Cervical; Cervix carcinoma; Chemicals; Complex; Cyclization; Derivation procedure; Development; Digit structure; Dipeptides; Drug Targeting; Exhibits; Family; Foundations; Goals; HL60; Heating; Hela Cells; Human; Hydroxamic Acids; Industry; Libraries; Literature; Malignant Neoplasms; Methodology; Methods; Molecular Conformation; Natural Products; Oxidants; Oximes; Periodicity; Pharmacology; Process; Property; Protocols documentation; Reaction; Reporting; Research; Route; Scientist; Series; Solvents; Source; Structure; Therapeutic; Virus; base; bioactive natural products; cytotoxic; diketopiperazine; drug discovery; fungus; innovation; interest; leukemia; novel; novel therapeutics; scaffold; screening

The goal of the proposed research is to provide direct and efficient synthetic access to biologically relevant structural motifs that are frequently found within complex natural products. Many naturally-occurring scaffolds exhibit inherent bioactivity against an assortment of bacteria, fungi, viruses and cancers and can serve as starting points for scientists to access more structurally complex and diverse libraries of compounds. Upon this derivation, they can be further screened against biological targets of interest in a quest to identify compounds with favorable pharmacological properties, and more importantly, efficacy against the target of interest. More specifically, the proposed research aims to develop a general, mild, and sustainable synthetic route to a series of difficult-to-access 2,5-diketopiperazines (2,5-DKPs) through an innovative ring expansion approach. The utility of the developed methodology will be realized by its application to complex molecule synthesis, specifically, to a total synthesis a family of natural products that have been shown to exhibit single-digit µM cytotoxic activity against human cervical and leukemia cancer cell lines. The successful synthesis of these molecules would provide authentic synthetic material that can be used in further biological studies. Furthermore, by employing readily available and inexpensive commodity chemicals in the ring expansion protocol to access DKPs, the proposed research seeks to facilitate the discovery of novel antibiotics, antiviral agents, and cancer therapeutics that contain the DKP scaffold.

拟议研究的目的是提供直接有效的合成访问 对于在复杂自然中经常发现的生物学相关结构基序 产品。许多自然出现的脚手架暴露了固有的生物活性 各种细菌，真菌，病毒和癌症，可以作为起点 科学家可以访问更结构复杂的化合物图书馆。之上 这种派生，可以进一步筛选它们的生物学目标 寻求识别具有良好药品的化合物，以及更多 重要的是，有效地针对感兴趣的目标。更具体地说，提议 研究旨在开发一系列一般，温和和可持续的合成途径 难以通过创新环扩展难以访问2,5-二甲苯 方法。开发方法的实用性将通过其应用于 特别是与总合成的复杂分子合成一个天然产物家族 已经显示出对人宫颈的单位细胞毒性暴露的µM细胞毒性活性 和白血病癌细胞系。这些分子的成功合成将 提供可用于进一步生物学研究的真实合成材料。 此外，通过使用随时可用且廉价的商品化学品 访问DKP的环形扩展协议，拟议的研究旨在促进 发现新型抗生素，抗病毒剂和癌症疗法的发现 DKP脚手架。