Indole Alkaloids and Phenazine Antibiotics: New Platforms for Drug Discovery

吲哚生物碱和吩嗪抗生素：药物发现的新平台

• 批准号: 10217189
• 负责人: Robert William Huigens
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217189
• 关键词: Antibiotics; Area; Award; Bacteria; Bacterial Infections; Biological; Biological Phenomena; Biological Process; Biology; Cancer Biology; Cell Survival; Cells; Cessation of life; Chemicals; Chemistry; Complex; Critical Pathways; Disease; Engineering; G-Protein-Coupled Receptors; Goals; Health; Human; In Vitro; Indole Alkaloids; Investigation; Lead; Libraries; Microbial Biofilms; Natural Products; Parents; Phenazines; Plasmodium falciparum; Prodrugs; Reaction; Series; Surface; System; Therapeutic Agents; United States; Yohimbine; bacterial community; base; chemical synthesis; drug discovery; experimental study; human disease; innovation; insight; methicillin resistant Staphylococcus aureus; oxidation; persistent bacterial infection; public health relevance; scaffold; small molecule; transcriptome sequencing

Indole Alkaloids and Phenazine Antibiotics: New Platforms For Drug Discovery Abstract: New small molecule probes and therapeutic agents are critical for the study and treatment of human disease. Our group is developing multiple chemical synthesis strategies to probe diverse biological phenomena related to human disease, including: bacterial biofilm viability, GPCR function, cancer biology and Plasmodium falciparum biology. We have developed a tryptoline-based ring distortion strategy using commercially available indole alkaloids (yohimbine and vincamine) as starting points for ring distortion, or the dramatic altering/reorganization of complex ring systems using chemoselective reactions. This approach has enabled the rapid synthesis of highly complex and diverse scaffolds for biological investigations and we have identified hit compounds in multiple disease-relevant areas pertinent to human health. Our hit compounds have gained new biological functions as their biological activities are unrelated to other scaffolds or their parent natural product, in essence, re-engineering of indole alkaloid’s chemical scaffolds and biological functions have been demonstrated. During this award, we will enhance the chemical diversity of our indole alkaloid ring distortion library by using C-H oxidation chemistry to install new synthetic handles for ring distortion and diastereoselective oxidative rearrangements to give new spirooxindole scaffolds with the ultimate goal of exploring disease-relevant chemical space with our probe molecules. In addition, our group has identified a series of halogenated phenazines (HP) that demonstrate potent biofilm-eradicating activities. These findings are significant as bacterial biofilms, or surface-attached bacterial communities, house persistent, non-replicating bacteria (persister cells) that demonstrate tolerance to all classes of antibiotics. Biofilms pose a significant threat to human health as 17 million new biofilm-associated bacterial infections occur annually that result in 550,000 deaths in the United States. We aim to use the HP small molecules we have developed as probe molecules in RNA-seq experiments with MRSA biofilms alongside other biofilm-killing agents to investigate biofilm viability with the goal of identifying new targets and cellular pathways critical to bacterial biofilms. In addition, we aim to develop a diverse array of HP prodrugs through chemical synthesis and in vitro biological studies. Providing new insights into the basic biology critical to biofilm cell viability and developing new biofilm-eradicating prodrugs could lead to ground-breaking cures for persistent bacterial infections. Huigens (PI) Project Summary/Abstract

吲哚生物碱和吩嗪抗生素：药物发现的新平台 抽象的： 新的小分子探针和治疗剂对于人类的研究和治疗至关重要 我们的小组正在开发多种化学合成策略来探索多种生物疾病。 与人类疾病相关的现象，包括：细菌生物膜活力、GPCR 功能、癌症 生物学和恶性疟原虫生物学我们开发了一种基于色氨酸的环畸变。 使用市售吲哚生物碱（育亨宾和长春胺）作为起点的策略 环畸变，或使用化学选择性对复杂环系统进行显着改变/重组 这种方法能够快速合成高度复杂和多样化的支架。 生物学研究，我们在多个疾病相关领域发现了热门化合物 我们的热门化合物因其生物学特性而获得了新的生物学功能。 活动与其他支架或其母体天然产物无关，本质上是对 吲哚生物碱的化学支架和生物功能已在该奖项中得到证明。 我们将通过使用C-H氧化来增强我们的吲哚生物碱环畸变库的化学多样性 化学安装新的合成手柄，用于环畸变和非对映选择性氧化 重新排列以提供新的螺吲哚支架，最终目标是探索与疾病相关的 此外，我们的团队还鉴定了一系列卤代化合物。 吩嗪 (HP) 具有有效的生物膜消除活性，这些发现具有重要意义。 细菌生物膜或表面附着的细菌群落，容纳持久的、非复制的细菌 对所有类别的抗生素表现出耐受性的（持久性细胞）构成了重大威胁。 每年发生 1700 万例新的生物膜相关细菌感染，导致人类健康 我们的目标是使用我们开发的 HP 小分子来帮助美国 55 万人死亡。 RNA-seq 实验中的探针分子与 MRSA 生物膜以及其他生物膜杀灭剂一起使用 研究生物膜的活力，目的是确定对生物膜至关重要的新靶点和细胞途径 此外，我们的目标是通过化学方法开发多种 HP 前药。 合成和体外生物学研究提供了对生物膜至关重要的基础生物学的新见解。 细胞活力的发展和新的生物膜消除前药可能会带来突破性的治疗方法 持续的细菌感染。 Huigens (PI) 项目总结/摘要