New Synthetic Strategies for Molecules that Target the Ribosome

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，小分子可以结合到定义明确的含有RNA的结构上，为治疗从癌症到细菌感染再到疟疾的各种疾病提供了一种策略。复合胺，其中含氮碳嵌入在一系列邻近的手性中心，很容易与核糖体结合，并在许多治疗中发现。然而，除了它们的有益活性外，由于它们与其他生物靶标的非选择性结合，它们经常表现出毒副作用。使用现有的合成方法调整复合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。这项提议的重点是开发一种通用的、统一的战略，用于高度官能化的胺的立体选择性合成。烯丙烯氮化反应的一个关键特征是在合成复合胺的过程中，对碳-杂原子键的类型进行了精确的控制，该键安装在三个烯基碳的每一个上。在任何想要的靶上，丙二烯衬底的轴向手性都能以极好的保真度转移到点手性。此外，可以从单一的外消旋丙烯前体中选择性地获得八个胺立体三元化合物中的任何一个。我们化学的这一独特功能最大限度地减少了保护基团、氧化状态变化和立体化学反转的使用，这些都困扰着目前的合成方法。联烯氮杂环化反应的灵活性和多功能性将改变复合胺的合成方式，获得新的化学空间，用于调节分子功能，解决与人类健康有关的重要问题。为了展示丙二烯氮杂环化作为合成各种生物活性胺的统一策略的多功能性，我们的方法学将首先应用于氨基糖苷类(AGs)的新类似物的合成，以降低它们的耳毒性，这一目标对囊性纤维化患者具有重要意义。在我们新方法的第二个应用中，将系统地研究与有效的氨基环戊醇--交替霉素--与核糖体的30S亚基结合所涉及的氢键相互作用。对有益的抗疟疾和抗肿瘤活动很重要的特定相互作用将被确定。最后，强效的蒽醌类抗生素 与阿霉素表现出的次要沟槽结合不同，与DNA的主要沟槽和次要沟槽结合的化合物将被合成。杂原子同一性和立体化学在这些化合物中存在的独特的双环氨基糖中的作用将通过明智的类似物的设计和制备来揭示。这将阐明这类蒽环类药物的心脏毒性和多药耐药性与阿霉素有何不同。我们的新分子的生物测试将与 UW小分子筛选和合成设施，该设施拥有开展我们工作所需的生物检测所需的资源。

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.