Synthetic Methods toward Antimicrobial tert-Alkylamino Carbocycles

抗菌叔烷基氨基碳环的合成方法

• 批准号: 7427248
• 负责人: Juan R Del Valle
• 金额: $ 14.14万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-24 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7427248
• 关键词: Alkaloids; Alkenes; Amines; Amino Acids; Amino Acyl-tRNA Synthetases; Anti-Infective Agents; Antibiotics; Area; Bacterial Antibiotic Resistance; Bacterial Proteins; Biological; Biological Factors; Biology; Carbamates; Carbon; Chemistry; Class; Code; Complex; Cyclization; Cyclopentane; DNA Sequence Rearrangement; Development; Enzymes; Evaluation; Facility Construction Funding Category; Family; Funding; Goals; Interdisciplinary Study; Ions; Laboratories; Lead; Libraries; Methodology; Methods; Modeling; Nitrogen; Numbers; Object Attachment; Pactamycin; Preparation; Prevalence; Process; Protein Biosynthesis; Reaction; Research; Rhodium; Structure; Structure-Activity Relationship; System; Transfer RNA; Work; altemicidin; analog; antimicrobial; base; chemical synthesis; design; experience; inhibitor/antagonist; nitrene; novel; novel strategies; novel therapeutics; prevent; programs; small molecule

DESCRIPTION (provided by applicant): Substituted tert-alkylamino carbocycles feature in a number of antimicrobial natural products, making methods for their chemical synthesis a key component in the discovery of new therapeutics. Our long-term goals are to develop new synthetic methodologies toward this privileged structural class, and to apply these methods to the discovery of small-molecule inhibitors of bacterial protein biosynthesis. To achieve these objectives, we have selected the altemicidin family of aminoacyl-tRNA synthetase inhibitors as target structures for subsequent structure-activity relationship studies. The principle challenges associated with the synthesis of altemicidin and its congeners are (1) the construction of a stereo-defined, substituted carbon- based ring and (2) the installation of an amine-bearing quaternary carbon center. The specific working hypothesis is that nitrene insertion reactions selective for ethereal C-H bonds can be carried out in the presence of other pendant functionalities, which will subsequently participate in intramolecular cyclizations to form tert-alkylamino carbocycles. We base this hypothesis on preliminary results in our laboratory showing that certain polyfunctional substrates undergo chemoselective nitrene insertion to give N-acyloxyaminals, known precursors to electrophilic iminium ions. Thus, our specific aims are to: (1) develop novel nitrene insertion-iminium ion carbocyclization strategies for the synthesis of carbocycles bearing quaternary centers. We will determine the scope of this reaction sequence within the context of biologically relevant targets and develop efficient tandem processes and novel rearrangement reactions. (2) Complete the total synthesis of altemicidin, SB-203207, and SB-203208. These studies will serve as a launch pad for the design and synthesis of structurally related inhibitors of aminoacyl-tRNA synthetases. 3. Build an externally funded interdisciplinary research program in the chemistry and biology of new small-molecule antibiotics. Synthetic obstacles often limit access to important natural lead compounds for biological evaluation. A target-driven effort toward the altemicidins will serve as a useful platform for the development of new approaches. Results emanating from this research should find wide application in the synthesis of other important antimicrobial natural products that have yet to be the subject of structure-activity relationship studies.

描述（由申请人提供）：替代的tert-Alkylamino carbocycles在许多抗菌天然产品中具有特征，使其化学合成的方法是发现新疗法的关键组成部分。我们的长期目标是针对这种特权结构类别开发新的合成方法，并将这些方法应用于发现细菌蛋白生物合成的小分子抑制剂。为了实现这些目标，我们选择了氨基酰基-TRNA合成酶抑制剂的高血菌素家族作为后续结构 - 活性关系研究的靶结构。与Altematiadin及其同类物的合成相关的原则挑战是（1）构建立体定义的，取代的碳基环，以及（2）安装胺含胺的Quaternary Carbon Center。特定的工作假设是，在存在其他吊坠功能的情况下，可以对空灵C-H键选择性进行硝酸一中的插入反应，随后将参与分子内环化以形成tert-烷基氨基氨基氨基碳纤维。我们以初步结果为基础，这是我们的实验室结果表明，某些多功能底物经历了化学选择性硝基插入，以获得N-乙酰氧基酰胺药物，即已知的亲电胺离子的前体。 因此，我们的具体目的是：（1）开发新型的硝基插入 - 离子离子碳环囊化策略，用于合成带有第四纪中心的碳纤维。我们将在生物学相关靶标的背景下确定此反应序列的范围，并开发有效的串联过程和新的重排反应。 （2）完成Altematiadin，SB-203207和SB-203208的总合成。这些研究将用作设计和合成氨基酰基-TRNA合成酶结构相关的抑制剂的发射台。 3。在新小分子抗生素的化学和生物学方面构建了一项外部资助的跨学科研究计划。 合成障碍通常会限制获得重要的自然铅化合物进行生物学评估。目标驱动的努力将成为高级植物的发展，这将是开发新方法的有用平台。这项研究的结果应在合成其他尚未成为结构活性关系研究的主题的其他重要抗菌天然产品中发现广泛的应用。