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

吲哚生物碱和苯嗪抗生素：药物发现的新平台 抽象的： 新的小分子问题和治疗剂对于人类的研究和治疗至关重要 疾病。我们的小组正在开发多种化学合成策略来探测潜水员生物学 与人类疾病有关的现象，包括：细菌生物膜生存能力，GPCR功能，癌症 生物学和恶性疟原虫生物学。我们已经开发了基于斜利的环形失真 使用市售吲哚生物碱（Yohimbine和Vincamine）作为起点的策略 环形失真，或使用化学选择性的复杂环系统的急剧改变/重组 反应。这种方法使高度复杂和潜水的脚手架的快速合成 生物学研究，我们已经确定了与多种疾病相关的地区的HIT化合物 与人类健康有关。我们的热门化合物已获得新的生物学功能作为其生物学 活动与其他脚手架或其父母自然产品无关，本质上是重新设计的 已经证明了吲哚生物碱的化学支架和生物学功能。在此奖励期间， 我们将使用C-H氧化来增强吲哚生物碱环失真文库的化学多样性 化学以安装新的合成手柄，用于环形失真和映射氧化物 重排以提供新的Spiooxindole脚手架，以探索与疾病相关的最终目标 带有探针分子的化学空间。此外，我们的小组已经确定了一系列卤素 表现出潜在的生物膜化学活性的苯胺（HP）。这些发现很重要，因为 细菌生物膜或表面附着的细菌群落，房屋持续，无重复的细菌 （持久细胞）证明对所有类别的抗生素的耐受性。生物膜构成重大威胁 对于人类健康，每年发生1700万新生物膜相关的细菌感染，这导致 美国550,000人死亡。我们的目标是使用我们开发的HP小分子 用MRSA生物膜与其他生物膜杀菌剂一起进行RNA-Seq实验中的探针分子 研究生物膜生存能力，目的是确定新目标和细胞途径至关重要 细菌生物膜。此外，我们旨在通过化学制造一系列HP前药阵列 合成和体外生物学研究。提供对生物膜至关重要的基本生物学的新见解 细胞活力和开发新的生物膜化学前药可能导致开创性的治疗方法 持续的细菌感染。 Huigens（PI）项目摘要/摘要