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(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和有效的方法来获得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。这项MIRA申请寻求合并两个由NIGMS资助的生产性项目，该项目广泛涉及手性、功能化生物活性小分子构建块的实验室制备。该计划的总体目标是开发新的合成化学平台，使快速和选择性地构建与生物医学应用直接相关的新结构成为可能。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，我们预计其效用将超越对感兴趣的目标的直接应用。与这种方法相叠加的是将重点放在催化将外消旋混合物转化为对映体产物的反应的子集上(动态动力学拆分，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。Jervine和DeoxoJervine是Hedgehog信号通路的抑制剂，半合成变种正在肿瘤学临床试验中进行评估。我们将利用类固醇Jerveratrum生物碱的结构作为灵感来开发新的对映体聚合反应，快速组装分子中具有挑战性的融合杂环部分。实施我们的战略的关键是认识到，目前的DKR方法仅限于相对较少的消旋机制。Mira赠款的一个重要部分是为了将DKR范例大幅扩展到以前从未被认为是对映体收敛候选的反应家族，特别是在可以快速组装分子复杂性的反应的背景下。我们对神经毒素河豚毒素的研究依赖于开发一种新的双重氧化/环加成级联序列，该序列可以快速组装高效合成所需的骨架、功能和立体化学复杂性。同样，虽然这种反应将使目标结构和同系物的构建变得容易，但预计更大的价值在于由于能够获得具有高水平独立可寻址功能的新的刚性模板家族而打开的新的化学空间。最后，我们将寻求开发涉及α-和β-二羰基结构的新的反应化学。含有这种官能团的化合物的特殊特性产生了独特的、使我们能够利用的化学，我们已经成功地和广泛地开发了这种化学。许多新的流形将在米拉拨款的支持下进行探索。总体而言，我们期待MIRA的研究活动将推动有机化学领域的发展，并通过提供对迄今为止未知或仅凭借低效和/或不切实际的方法才能获得的结构的便捷访问，在生物医学努力中发挥作用。