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：
10238079
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/10238079
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

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

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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：我们在上一个资金期间的工作受到分子固有的合成挑战的启发直接与核糖体结合或间接影响其功能。结构活动关系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，无法灵活地改变参与H-的关键胺和酒精群的定位，立体化学和空间环境与结合位点的键合或静电相互作用；改变烷基和芳基的情况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上的合成天然产物中存在的复合胺“三合会”，抑制蛋白质合成，包括氨基辛醇，蒽环类动物和四环素。这使我们能够构建受生物活性自然启发的“不自然产品” 产品，可以在以下位置实现多样性的产品：1）安装在胺“三合会”构件中的杂原子，2）三个连续的杂化SP3碳中心之间的立体化学关系三合会以及3）官能化的碳和异环脚手架。一个> 1000个独特化合物的库新颖的胺化学空间显示出明显的立体化学复杂性已显示出有希望的活动抗药性疟疾和结核病，Chaga病，肝细胞癌和其他生物靶标。这种更新是基于我们在确保复杂，唯一功能化的胺图案的专业知识上建立的，以调查主要通过与核糖体。潜在抗疟疾天然产物jodyamycin的类似物将准备探测如何结合核糖体受到影响；这些研究是设计显示的更简单的合成胺支架的关键类似的生物活性，但对寄生虫与真核线粒体核糖体的选择性更好，降低了毒性，不太倾向于发展抵抗力。以同样的方式，我们在复杂胺合成方面的专业知识将应用于降低毒性和多药耐药性的“混合”蒽环类药物的设计广泛使用的抗肿瘤药物阿霉素（DOX）和其他相关药物对治疗癌症。我们已经获得了几位合作者的帮助，以评估化合物的生物学活动并洞悉第二代图书馆的设计，包括Eli Lilly Open Innovation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。