Synthetic approaches to complex amines that inhibit protein synthesis by impacting the ribosome

项目摘要/摘要： 我们在前一个资助期的工作是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-活性关系研究很困难 在这些类别的分子中，由于缺乏灵活的合成方法来实现灵活的改变 关键的胺和醇基团的位置、立体化学和空间环境 与结合部位的键合或静电相互作用；改变烷基和芳基也是如此， 参与疏水或π-π互动。我们的多种方法简化了立体化学的合成 天然产物中存在复杂的胺“三联体”，可抑制蛋白质合成，包括氨基环醇， 蒽环类和四环素类。这使我们能够构建受生物活性天然物质启发的“非天然产品” 可在以下方面实现多样性的产品：1)安装在胺“三位一体”构件中的杂原子；2) 三个连续的、含杂原子的SP3碳中心之间的立体化学关系 三联体，以及3)高官能化碳杂环支架。中的&gt；1000个独特化合物的库 显示出显著的立体化学复杂性的新型胺化学空间显示出良好的活性 对抗抗药性疟疾和结核病、查加氏病、肝细胞癌和其他 生物靶标。 这一更新建立在我们确保复杂的、密集功能化的胺主题以进行研究的专业知识的基础上 影响蛋白质合成的分子中的结构-活性关系，主要是通过与 核糖体。强效抗疟疾天然产物交吉霉素的类似物将准备探索如何结合 对核糖体的影响；这些研究是设计更简单的合成胺支架的关键，表明 生物活性相似，但对寄生线粒体核糖体的选择性更好，毒性更低， 更不容易产生抵抗力。同样，我们在复合胺合成方面的专业知识将 可应用于设计可减轻毒性和多药耐药性的杂化蒽环类药物。 广泛使用的抗肿瘤药物阿霉素(DOX)等相关药物对治疗恶性黑色素瘤具有重要意义。 癌症。我们已经获得了几位合作者的帮助，以评估我们化合物的生物活性。 并提供对第二代图书馆设计的洞察，包括礼来公司的开放式创新计划， 葛兰素史克(正在进行中)，Corteva农业科学公司，几位学术同事(Taifo Mahm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。

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.