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: 10451729
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451729
• 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

吲哚生物碱和吩嗪类抗生素：药物发现的新平台 摘要： 新型小分子探针和治疗剂对于人类疾病的研究和治疗至关重要 疾病我们的团队正在开发多种化学合成策略，以探测各种生物学特性。 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托啉的环失真 使用市售吲哚生物碱（育亨宾和长春胺）作为起始点的策略， 环扭曲，或使用化学选择性的复杂环系统的戏剧性改变/重组 反应.这种方法使得能够快速合成高度复杂和多样化的支架， 生物调查，我们已经确定了命中化合物在多个疾病相关领域 与人类健康有关。我们的热门化合物已经获得了新的生物功能，因为它们的生物活性 活动与其他支架或其母体天然产物无关，本质上， 吲哚类生物碱的化学骨架和生物学功能已得到证实。在本次颁奖期间， 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 化学安装新的合成处理环扭曲和非对映选择性氧化 重组，以获得新的螺羟吲哚支架，最终目标是探索疾病相关的 化学空间与我们的探针分子。此外，我们的小组还确定了一系列卤代 吩嗪（HP），其表现出有效的生物膜根除活性。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 （持久细胞），表现出对所有类别的抗生素的耐受性。生物膜构成了重大威胁 每年发生1700万例新的生物膜相关细菌感染， 美国有55万人死亡。我们的目标是使用我们开发的HP小分子作为 在RNA-seq实验中使用MRSA生物膜以及其他生物膜杀伤剂的探针分子， 研究生物膜的活力，目的是确定新的目标和细胞途径， 细菌生物膜此外，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。为生物膜关键的基础生物学提供新的见解 细胞活力和开发新的生物膜消除前药可能会导致突破性的治疗， 持续性细菌感染。 Huigens（PI）项目概要/摘要

项目成果

Modular Synthetic Routes to Fluorine-Containing Halogenated Phenazine and Acridine Agents That Induce Rapid Iron Starvation in Methicillin-Resistant Staphylococcus aureus Biofilms.

• DOI: 10.1021/acsinfecdis.1c00402
• 发表时间: 2022-02-11
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Liu, Ke;Brivio, Massimiliano;Xiao, Tao;Norwood, Verrill M.;Kim, Young S.;Jin, Shouguang;Papagni, Antonio;Vaghi, Luca;Huigens, Robert W. I. I. I. I. I. I.
• 通讯作者: Huigens, Robert W. I. I. I. I. I. I.

The Path to New Halogenated Quinolines With Enhanced Activities Against Staphylococcus epidermidis.

• DOI: 10.1177/1178636118808532
• 发表时间: 2018-01-01
• 期刊: Microbiology insights
• 作者: Huigens, Robert W 3rd

A Modular Synthetic Route Involving N-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents.

• DOI: 10.1021/acs.jmedchem.1c00168
• 发表时间: 2021-06-10
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Yang H;Kundra S;Chojnacki M;Liu K;Fuse MA;Abouelhassan Y;Kallifidas D;Zhang P;Huang G;Jin S;Ding Y;Luesch H;Rohde KH;Dunman PM;Lemos JA;Huigens RW 3rd
• 通讯作者: Huigens RW 3rd

Re-Engineering of Yohimbine's Biological Activity through Ring Distortion: Identification and Structure-Activity Relationships of a New Class of Antiplasmodial Agents.

通过环扭曲重新设计育亨宾的生物活性：一类新型抗疟原虫的鉴定和结构-活性关系。

• DOI: 10.1021/acsinfecdis.9b00380
• 发表时间: 2020
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Paciaroni,NicholasG;Perry2nd,DavidL;Norwood4th,VerrillM;Murillo-Solano,Claribel;Collins,Jennifer;Tenneti,Srinivasarao;Chakrabarti,Debopam;Huigens3rd,RobertW
• 通讯作者: Huigens3rd,RobertW

Transcript Profiling of Nitroxoline-Treated Biofilms Shows Rapid Up-regulation of Iron Acquisition Gene Clusters.

• DOI: 10.1021/acsinfecdis.2c00206
• 发表时间: 2022-08-12
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Liu, Ke;Abouelhassan, Yasmeen;Zhang, Yanping;Jin, Shouguang;Huigens, Robert W., III
• 通讯作者: Huigens, Robert W., III