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: 9268689
• 负责人: Jennifer Marie Schomaker
• 金额: $ 17万
• 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/9268689
• 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; base; cystic fibrosis patients; design; flexibility; hearing impairment; improved; meetings; novel; ototoxicity; oxidation; propadiene; 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（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，小分子可以与定义明确的含有rna的结构结合，从而为治疗从癌症到细菌感染再到疟疾等疾病提供一种策略。含氮碳被嵌入一系列相邻的手性中心的复合胺，很容易与核糖体结合，在许多治疗方法中都有发现。然而，除了它们的有益作用外，它们往往由于与其他生物靶点的非选择性结合而表现出毒副作用。使用现有的合成方法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。这一建议的重点是发展一个多功能的，统一的战略立体选择性合成高功能化胺。丙烯叠氮化的一个关键特征是，在合成复合胺的过程中，对安装在三个丙烯碳上的碳杂原子键的类型进行了精确的控制。烯基底物的轴向手性在任何期望的目标中以极好的保真度转移到点手性。此外，可以从单个外消旋烯前体选择性地获得八种胺立体三合体中的任何一种。我们化学的这种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反转困扰着当前的合成方法。烯叠氮化的灵活性和多功能性将改变复合胺的合成方式，为调节分子功能提供新的化学空间，以解决与人类健康有关的重要问题。为了展示丙烯叠氮化作为合成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中，将对强效氨基环戊二醇jogyamycin与核糖体30S亚基结合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。最后是强效的蒽醌类抗生素