New Synthetic Strategies for Molecules that Target the Ribosome

针对核糖体的分子的新合成策略

• 批准号: 9313298
• 负责人: Jennifer Marie Schomaker
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/9313298
• 关键词: Address; Adverse effects; Amination; 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; base; cystic fibrosis patients; design; flexibility; hearing impairment; improved; novel; ototoxicity; oxidation; propadiene; public health relevance; scaffold; screening; small molecule; stereochemistry; sugar; tool; tumor

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，长期以来被认为缺乏结构复杂性。然而，最近的研究表明，小分子可以结合到定义明确的含RNA的结构，为治疗从癌症到细菌感染再到疟疾的疾病提供一种策略。复合胺，其中含氮碳嵌入在一系列相邻的手性中心中，容易与核糖体结合，并在许多治疗中发现。然而，除了它们的有益活性之外，它们通常由于与其他生物靶标的非选择性结合而表现出毒副作用。使用现有的合成方法来调整复杂胺的反应性是具有挑战性的，这阻碍了识别仅与核糖体结合的分子的努力。该建议的重点是发展一个通用的，统一的战略高度官能化胺的立体选择性合成。 丙二烯氮丙啶化的一个关键特征是对碳-杂原子键的类型的精确控制，该碳-杂原子键安装在我们的复杂胺的合成中的三个丙二烯碳中的每一个上。联烯基片的轴向手性在任何期望的目标中以优异的保真度转移为点手性。此外，可以从单一外消旋丙二烯前体实现选择性地获得八种胺立体三单元中的任一种。我们化学的这一独特功能最大限度地减少了保护基团的使用，氧化态变化和立体化学转化，这些都困扰着当前的合成方法。丙二烯氮丙啶化的灵活性和多功能性将改变合成复杂胺的方式，以获得新的化学空间来调节分子功能，以解决与人类健康相关的重要问题。 为了展示丙二烯氮丙啶化作为合成不同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氨基糖苷类（AG）的新型类似物的合成，以降低其耳毒性，这一目标对囊性纤维化患者具有重要意义。在我们的新方法的第二个应用程序中，将进行一个系统的研究的氢键相互作用，参与绑定的一个有效的aminocyclopentitol，乔吉霉素，核糖体的30 S亚基。将确定有益的抗疟和抗肿瘤活性的重要的特定相互作用。最后，有效的蒽醌抗生素 与多柔比星所表现出的小沟结合相反，将合成与DNA的大沟和小沟都结合的多柔比星。杂原子的身份和立体化学的作用，在这些化合物中存在的独特的双环氨基糖将通过明智的设计和制备类似物解开。这将阐明这类蒽环类药物的心脏毒性和多药耐药性与多柔比星的不同。我们的新分子的生物测试将与 华盛顿大学小分子筛选和合成设施，它有必要的资源，进行我们的工作所需的生物测定。