Synthetic approaches to complex amines that inhibit protein synthesis by impacting the ribosome

通过影响核糖体抑制蛋白质合成的复杂胺的合成方法

基本信息

批准号：
10470244
负责人：
Jennifer Marie Schomaker
金额：
$ 26.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470244
关键词：
3-hydroxybutanal Alcohols Amination Amines Amino Sugars Anthracycline Antibiotics Antimalarials Binding Binding Sites Biological Biological Assay Carbon Cardiotoxicity Cells Chagas Disease Chemicals Chiroptera Collaborations Complex Coupled Coupling DNA Disease Doxorubicin Drug resistance Electrostatics Environment Eukaryotic Cell Evaluation Exhibits Funding Generations Hybrids Hydrogen Bonding Hydrophobicity Laboratories Lead Libraries Major Groove Malaria Menogaril Methods Minor Groove Mitochondria Multi-Drug Resistance Natural Products Pharmaceutical Chemistry Pharmaceutical Preparations Positioning Attribute Primary carcinoma of the liver cells Protein Biosynthesis Resistance development Ribosomes Role Route Secure Structure-Activity Relationship Tetracyclines Therapeutic Therapeutic Agents Toxic effect Triad Acrylic Resin Tuberculosis Universities Wisconsin Work analog anticancer activity antitumor agent antitumor drug base behavior influence bioactive natural products cancer therapy computer studies design drug discovery experience experimental study flexibility functional group insight interest novel open innovation pathogen professor programs propadiene scaffold small molecule stereochemistry tumor

项目摘要

Project Summary/Abstract: Our work in the previous funding period was inspired by synthetic challenges inherent in molecules that directly bind to the ribosome or indirectly impact its function. Structure-activity relationship studies are difficult in these classes of molecules, due to lack of flexible synthetic methods to enable flexible changes to the positioning, stereochemistry and steric environments of key amine and alcohol groups that engage in H- bonding or electrostatic interactions with the binding site; the same is true for altering alkyl and aryl groups that participate in hydrophobic or π-π interactions. Our versatile methods streamline syntheses of stereochemically complex amine 'triads' present in natural products that inhibit protein synthesis, including aminocyclitols, anthracyclines, and tetracyclines. This enables us to construct 'unnatural products' inspired by bioactive natural products, where diversity can be achieved in: 1) heteroatoms installed in the amine 'triad' building blocks, 2) stereochemical relationships amongst the three contiguous, heteroatom-bearing sp3 carbon centers of the triad, and 3) densely functionalized carbo- and heterocyclic scaffolds. A library of >1000 unique compounds in novel amine chemical space displaying significant stereochemical complexity has shown promising activities against drug-resistant malaria and tuberculosis, Chaga's disease, hepatocellular carcinoma, and other biological targets. This renewal builds on our expertise in securing complex, densely functionalized amine motifs to investigate structure-activity relationships in molecules that impact protein synthesis, primarily through interactions with the ribosome. Analogs of the potent antimalarial natural product jogyamycin will be prepared to probe how binding to the ribosome is impacted; these studies are key to the design of simpler synthetic amine scaffolds that show similar bioactivity, but better selectivity for parasitic vs. eukaryotic mitochondrial ribosomes, lowered toxicity, and less propensity to develop resistance. In the same manner, our expertise in complex amine synthesis will be applied to the design of 'hybrid' anthracyclines that mitigate the toxicity and multi-drug resistance seen in the widely-used antitumor drug doxorubicin (DOX) and other related drugs of significance to the treatment of cancer. We have secured the aid of several collaborators to assess the biological activities of our compounds and provide insight into the design of 2nd-generation libraries, including the Eli Lilly Open Innovation program, GSK (in progress), Corteva Agrisciences, several academic colleagues (Prof. Taifo Mahmud, Prof. Dev Arya, Prof. Silvia Cavagnero, Dr. Desiree Bates), and the University of Wisconsin Medicinal Chemistry Center.

项目摘要/摘要：我们在上一个资助期的工作受到分子固有的合成挑战的启发，这些挑战直接结合核糖体或间接影响其功能的研究很困难。在这些类别的分子中，由于缺乏灵活的合成方法来实现灵活的改变参与 H- 的关键胺和醇基团的定位、立体化学和空间环境与结合位点的键合或静电相互作用；对于改变烷基和芳基也是如此；参与疏水或 π-π 相互作用我们的多功能方法简化了立体化学的合成。天然产物中存在的复杂胺“三联体”会抑制蛋白质合成，包括氨基环醇，这使我们能够构建受生物活性天然物质启发的“非天然产品”。产品的多样性可以通过以下方式实现：1) 安装在胺“三元组”结构单元中的杂原子，2) 三个连续的、带有杂原子的sp3碳中心之间的立体化学关系三联体，以及 3) 密集功能化的碳环和杂环支架包含超过 1000 种独特化合物的库。具有显着立体化学复杂性的新型胺化学空间已显示出有前景的活性对抗耐药性疟疾和结核病、白桦茸病、肝细胞癌等生物目标。此次更新建立在我们在确保复杂、密集功能化的胺基序进行研究方面的专业知识之上影响蛋白质合成的分子的结构-活性关系，主要是通过与将制备有效的抗疟天然产物乔贾霉素的类似物来探究如何结合。这些研究是设计更简单的合成胺支架的关键相似的生物活性，但对寄生线粒体核糖体的选择性比真核线粒体核糖体更好，毒性更低，以同样的方式，我们在复杂胺合成方面的专业知识将减少产生耐药性的可能性。应用于“混合”蒽环类药物的设计，减轻其毒性和多药耐药性广泛使用的抗肿瘤药物阿霉素（DOX）和其他对治疗肿瘤具有重要意义的相关药物我们已经获得了几位合作者的帮助来评估我们化合物的生物活性。并提供对第二代图书馆设计的见解，包括礼来开放创新计划， GSK（正在进行中）、Corteva Agrisciences、几位学术同事（Taifo Mahmud 教授、Dev Arya 教授、 Silvia Cavagnero 教授、Desiree Bates 博士）和威斯康星大学药物化学中心。