New Synthetic Strategies for Molecules that Target the Ribosome

针对核糖体的分子的新合成策略

基本信息

批准号：
8745078
负责人：
Jennifer Marie Schomaker
金额：
$ 21.13万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8745078
关键词：
Address Adverse effects Amines Amino Sugars Aminoglycosides Anthracycline Antibiotics Anthracyclines Anthraquinones Antibiotic Resistance Antibiotics Antimalarials Bacterial Infections Binding Biological Biological Assay Biological Testing Caliber Carbon Cardiotoxicity Chemicals Chemistry Clinical Collaborations Complex Cyclopentane DNA Development Disease Doxorubicin Ear Electrostatics Enzymes Evaluation Exhibits Fluorine Gentamicins Goals Halogens Health Human Hydrogen Bonding Intention Kidney Lead Libraries Light Major Groove Malaria Malignant Neoplasms Methodology Methods Minor Groove Modification Molecular Multi-Drug Resistance Nitrogen Pharmaceutical Preparations Plague Positioning Attribute Preparation Protein Biosynthesis Proteins Public Health RNA Resources Ribosomes Role Route Structure Testing Therapeutic Therapeutic Agents Toxic effect Transducers Work analog antitumor agent arugomycin base cystic fibrosis patients design flexibility hearing impairment improved meetings novel ototoxicity oxidation propadiene scaffold screening small molecule stereochemistry sugar tool tumor

项目摘要

DESCRIPTION (provided by applicant): RNA is an important messenger between DNA and proteins and was long thought to be lacking in structural complexity. However, recent work has shown that small molecules can bind to well-defined RNA-containing structures to provide a strategy for treating diseases ranging from cancer to bacterial infections to malaria. Complex amines, where the nitrogen-bearing carbon is embedded in an array of neighboring chiral centers, readily bind to the ribosome and are found in many therapeutics. However, in addition to their beneficial activities, they often exhibit toxic side effects due to non-selective binding o other biological targets. Tuning reactivity in complex amines is challenging using existing synthetic methodology, hampering efforts to identify molecules that bind only to the ribosome. This proposal focuses on developing a versatile, unified strategy for the stereoselective synthesis of highly functionalized amines. A key feature of allene aziridination is the exquisite control over the type of carbon-heteroatom bond that is installed at each one of the three allene carbons in the synthesis of our complex amines. The axial chirality of the allene substrate is transferred to point chirality in any desired target with excellent fidelity. In addition, selectiv access to any one of eight amine stereotriads can be achieved from a single racemic allene precursor. This unique feature of our chemistry minimizes the use of protecting groups, oxidation state changes and stereochemical inversions that plague current synthetic approaches. The flexibility and versatility of allene aziridination will transform the ways in whic complex amines are synthesized to access novel chemical space for tuning molecular function to address important questions related to human health. To showcase the versatility of allene aziridination as a unified strategy towards the synthesis of diverse bioactive amines, our methodology will first be applied to the synthesis of novel analogues of the aminoglycosides (AGs) to decrease their ototoxicity, a goal having important implications for cystic fibrosis patients. In a second application of our new methods, a systematic study of the hydrogen bonding interactions involved in binding of a potent aminocyclopentitol, jogyamycin, to the 30S subunit of the ribosome, will be carried out. Specific interactions important for the beneficial antimalarial and antitumor activities will be identified. Finally, potent anthraquinone antibiotics that bind to both the major and minor grooves of DNA, in contrast to the minor groove binding exhibited by doxorubicin, will be synthesized. The role of the heteroatom identity and stereochemistry in the unique bicyclic aminosugars present in these compounds will be unraveled through the judicious design and preparation of analogues. This will shed light on how the cardiotoxicity and multi-drug resistance in this class of anthracyclines differs from doxorubicin. The biological testing of our new molecules will carried out in collaboration with the UW Small Molecule Screening and Synthesis Facility, which has resources necessary to undertake the biological assays needed in our work.

描述（由申请人提供）：RNA是DNA和蛋白质之间的重要信使，长期以来人们认为缺乏结构复杂性。然而，最近的工作表明，小分子可以与明确定义的RNA结构结合，以提供从癌症到细菌感染再到疟疾的疾病的策略。复杂的胺（含氮的碳嵌入在相邻的手性中心阵列中）很容易结合到核糖体中，并且在许多疗法中都发现。但是，除了其有益的活动外，由于非选择性结合O其他生物学靶标，它们经常表现出有毒的副作用。复杂胺中的反应性使用现有的合成方法，阻碍了仅与核糖体结合的分子的努力。该提案着重于制定一种多功能，统一的策略，用于高度功能化胺的立体选择性合成。 Allene Aziridination的一个关键特征是对我们复合胺的合成中三个Allene Carbons中的每个碳纤维键的类型进行精致的控制。 Allene底物的轴向手性转移到具有出色的保真度的任何所需目标中的点手性。此外，可以从单个外星人的阿琳前体来实现对八个胺立体定位中任何一个的选择访问。我们的化学的独特特征最大程度地减少了保护基团的使用，氧化状态的变化和陷入困扰当前合成方法的立体化学反转。 Allene Aziridination的灵活性和多功能性将改变Whic Complex胺的方式，以获取新的化学空间来调整分子功能，以解决与人类健康有关的重要问题。为了展示Allene Aziridination作为综合多种生物活性胺的统一策略的多功能性，我们的方法将首先应用于合成氨基糖苷（AGS）的新型类似物的合成，以减少其耳毒性，这是对静脉纤维化患者具有重要意义的目标。在我们的新方法的第二次应用中，将对有效氨基类乙醇（Jogyamycin）与核糖体的30年代亚基的结合涉及的氢键相互作用进行系统研究。将确定对有益的抗疟疾和抗肿瘤活性重要的特定相互作用。最后，有效的蒽醌抗生素与阿霉素所表现出的小凹槽结合相反，将与DNA的主要和小凹槽结合。杂原子身份和立体化学在这些化合物中存在的独特的氨基糖中的作用将通过明智的设计和类似物的准备来揭示。这将阐明这类蒽环类药物中的心脏毒性和多药耐药性与阿霉素不同。我们的新分子的生物测试将与 UW小分子筛选和合成设施，它具有进行我们工作中需要的生物学测定所需的资源。