Indole Alkaloids and Phenazine Antibiotics: New Platforms for Drug Discovery

吲哚生物碱和吩嗪类抗生素：药物发现的新平台 摘要： 新的小分子探针和治疗剂对人类癌症的研究和治疗至关重要 疾病。我们小组正在开发多种化学合成策略，以探索不同的生物 与人类疾病有关的现象，包括：细菌生物膜活力，GPCR功能，癌症 生物学与恶性疟原虫生物学我们已经开发出一种基于色氨酸的环扭曲 使用商业上可用的吲哚生物碱(育亨宾和长春花碱)作为起点的战略 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。这种方法使得快速合成高度复杂和多样化的支架成为可能 生物调查和我们已经在多个与疾病相关的领域中发现了命中化合物 与人类健康有关。我们的热门化合物获得了新的生物功能，因为它们的生物 活动与其他支架或其母天然产物无关，本质上是对 吲哚生物碱的化学支架和生物学功能已得到证实。在颁奖过程中， 我们将通过C-H氧化来增强我们的吲哚生物碱环扭曲文库的化学多样性 化学公司将安装新的合成手柄，用于环扭曲和非对映选择性氧化 重新排列以提供新的螺氧吲哚支架，最终目标是探索与疾病相关的 化学空间与我们的探测分子。此外，我们小组还鉴定了一系列卤代化合物 吩嗪类(HP)，显示出强大的生物被膜消除活性。这些发现具有重要意义，因为 细菌生物膜，或表面附着的细菌群落，容纳着持久的、不可复制的细菌 (持久细胞)对所有类别的抗生素都表现出耐受性。生物膜构成了一个重大威胁 对人类健康的影响，因为每年发生1700万新的与生物膜相关的细菌感染，导致 美国有55万人死亡。我们的目标是将我们开发的惠普小分子用作 使用MRSA生物膜和其他生物膜杀伤剂进行RNA-SEQ实验中的探针分子 研究生物膜的活性，目标是确定新的靶点和细胞途径，这些途径对 细菌生物膜。此外，我们的目标是通过化学方法开发一系列多样化的惠普前药 合成和体外生物学研究。提供对生物膜至关重要的基础生物学的新见解 细胞活性和开发新的消除生物膜的前药可能导致突破性的治疗 持续的细菌感染。 惠根斯(PI)项目摘要/摘要

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