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

吲哚类生物碱和非那嗪类抗生素：药物发现的新平台