Synthesis of Bioactive Small Molecule Building Blocks

生物活性小分子构件的合成

• 批准号: 9266444
• 负责人: Jeffrey S Johnson
• 金额: $ 42.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266444
• 关键词: Alkaloids; Architecture; Breathing; Chemicals; Chemistry; Clinical Oncology; Clinical Trials; Communities; Complex; Development; Evaluation; Family; Funding; Goals; Grant; Kinetics; Laboratories; Methodology; Methods; Molecular; National Institute of General Medical Sciences; Natural Products Chemistry; Neurotoxins; Organic Chemistry; Outcome; Preparation; Reaction; Research Activity; Resolution; Steroids; Structure; Synthesis Chemistry; Tetrodotoxin; Transcend; Variant; bioactive natural products; cycloaddition; design; direct application; functional group; inhibitor/antagonist; interest; invention; next generation; oxidation; programs; public health relevance; racemization; skeletal; small molecule; small molecule therapeutics; smoothened signaling pathway

 DESCRIPTION (provided by applicant): A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This MIRA application seeks to merge two productive NIGMS-funded projects broadly concerned with the laboratory preparation of chiral, functionalized bioactive small molecule building blocks. The general goal of this program is to develop new synthetic chemistry platforms that will enable the rapid and selective construction of new structures of immediate relevance for biomedical applications. We will use the structures of architecturally and functionally complex bioactive natural products as an inspiration for the invention of new synthetic methods whose utility we expect to transcend the direct application to the target of interest. Overlaid with this approach will be a focus on a subset of reactions that catalytically convert racemic mixtures to enantiopure products (dynamic kinetic resolution, DKR). Thus, a symbiotic loop between natural product chemistry and new reaction development is a projected outcome. Jervine and deoxojervine are inhibitors of the hedgehog signaling pathway and semisynthetic variants are under evaluation in oncology clinical trials. We will use the structure of the steroidal jerveratrum alkaloids as an inspiration to develop new enantioconvergent reactions that rapidly assemble the challenging fused heterocyclic portion of the molecule. The key to implementation of our strategy is the recognition that current DKR methodology is limited to a relatively small number of racemization mechanisms. A significant part of the MIRA grant is designed to dramatically expand the DKR paradigm into families of reactions that have never before been considered as candidates for enantioconvergence, particularly in the context of reactions that can rapidly assemble molecular complexity. Our approach to the neurotoxin tetrodotoxin hinges on the development of a new twofold oxidation/cycloaddition cascade sequence that quickly assembles the skeletal, functional, and stereochemical complexity that will be required for an efficient synthesis. Again, while this reaction will enable facile construction of the target structure and congeners, the greater value is projected to lie in the new chemical space that opens as a consequence of having access to a new family of rigid templates with a high level of independently addressable functionality. Finally, we will seek to develop new reaction chemistry involving α- and β-dicarbonyl structures. The special features of compounds containing such functional groups engender unique and enabling chemistry that we have successfully and extensively exploited. Many new manifolds will be explored under the aegis of the MIRA grant. Collectively, we expect that the MIRA research activities will advance the field of organic chemistry and be of use in biomedical endeavors by providing facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical.

 描述（由申请人提供）：创建下一代小分子疗法的一个重大障碍是缺乏通用且有效的方法来获取某些立体化学致密结构，这些结构包含对生物活性重要的功能。 NIGMS 资助的项目广泛涉及手性、功能化生物活性小分子结构单元的实验室制备，该项目的总体目标是开发新的合成化学平台，从而能够快速、选择性地构建与直接相关的新结构。我们将利用结构和功能复杂的生物活性天然产物的结构作为发明新合成方法的灵感，我们期望其实用性超越对感兴趣目标的直接应用，这将是我们关注的重点。催化将外消旋混合物转化为对映体纯产物的反应的子集（动态动力学解析，DKR）因此，天然产物化学和新反应开发之间的共生循环是预计的结果。刺猬信号通路的抑制剂和半合成变体正在肿瘤学临床试验中进行评估，我们将利用甾体姜黄素生物碱的结构作为开发新的对映体收敛反应的关键，该反应可以快速组装分子中具有挑战性的稠合杂环部分。我们战略的实施是认识到当前的 DKR 方法仅限于相对较少的外消旋机制。 MIRA 拨款的很大一部分旨在大幅扩展外消旋机制。 DKR 范式融入了以前从未被认为是对映体收敛候选反应的反应家族，特别是在可以快速组装分子复杂性的反应中。我们对神经毒素河豚毒素的方法取决于新的双重氧化/环加成级联序列的开发。快速组装有效合成所需的骨架、功能和立体化学复杂性，同时该反应将能够轻松构建目标结构和。预计更大的价值在于新的化学空间，该空间是由于获得具有高水平独立可寻址功能的新刚性模板系列而打开的。最后，我们将寻求开发涉及 α 的新反应化学。 - 和 β-二羰基结构。含有此类官能团的化合物的特殊特征产生了独特且有利的化学作用，我们已经在 MIRA 资助的支持下进行了许多新的研究。研究活动通过提供迄今为止未知或只能通过低效和/或不切实际的方法才能获得的结构，将推动有机化学领域的发展，并可用于生物医学领域。