Stereoselective Synthesis of aza-Sulfur(VI) Motifs as Design Elements for Drug Discovery

氮杂硫 (VI) 基序的立体选择性合成作为药物发现的设计元素

• 批准号: 2753619
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2753619
• 关键词: Stereoselective; Synthesis; aza; Sulfur; VI

The incorporation of "unusual" functional groups in medicinal chemistry provides access to new areas of biologically relevant chemical and intellectual property space. This is particularly attractive for groups that can provide improved physicochemical properties or novel replacement groups. In this context, aza-sulfur (VI) motifs (containing an S=N group) have emerged as offering an attractive balance of properties and controlled three-dimensional frameworks, as well as acting as bioisosteres for other important functionality. This is most notable in sulfoximines, which feature in AstraZeneca's ATR inhibitor AZD6738 (Ceralasertib), in clinical trials for various advanced cancers. This project will develop new stereocontrolled methods to generate aza-sulfur (VI) motifs that are predicted to provide valuable design options in medicinal chemistry. Methods will be developed that provide more facile access to these underexplored motifs and control the absolute 3-D shape to enable medicinal chemists to readily incorporate these into discovery programmes. New stereocontrolled processes will be developed for sulfoximines, sulfonimidamides, and sulfondiimine groups. Furthermore functionalisation of the respective nitrogen atoms will be developed to demonstrate tunability of the global properties, and the preparation of cyclic derivatives. This project fits with the EPSRC priority of transforming healthcare. We will develop facile access to new replacement groups for use in drugs and chemical probes, and expand the design options for medicinal chemists. The project will take two approaches to the asymmetric synthesis of the targeted structures by S-N and S-C bond formation, to maximise flexibility to incorporate these derivatives in a drug discovery programme, and to directly access to either configuration at the sulfur atom. Fundamental studies on the intermediates in these processes will provide new mechanistic insights. Finally we will explore the properties of the generated compounds.

在药物化学中加入“不寻常的”官能团提供了进入生物相关化学和知识产权空间新领域的途径。这对于能够提供改进的物理化学性质或新颖的替代基团的基团特别有吸引力。在这种情况下，氮杂-硫（VI）基序（包含S=N基团）已经出现，提供了一种有吸引力的性质平衡和受控的三维框架，以及作为其他重要功能的生物同位体。这在亚砜亚胺中最为显著，阿斯利康的ATR抑制剂AZD6738 （Ceralasertib）在各种晚期癌症的临床试验中发挥了重要作用。该项目将开发新的立体控制方法来生成偶氮-硫（VI）基序，预计将为药物化学提供有价值的设计选择。将开发方法，提供更方便地访问这些未被探索的基序，并控制绝对的三维形状，使药物化学家能够轻松地将它们纳入发现计划。新的立体控制工艺将用于亚砜亚胺、磺酰酰胺和磺酰二亚胺基团。此外，将开发相应氮原子的功能化，以证明整体性质的可调性，并制备环衍生物。该项目符合EPSRC改革医疗保健的优先事项。促进新型药物和化学探针替代基团的便捷获取，扩大药物化学家的设计选择。该项目将采用两种方法通过S-N和S-C键形成目标结构的不对称合成，以最大限度地提高将这些衍生物纳入药物发现计划的灵活性，并直接访问硫原子上的任何一种配置。对这些过程中中间体的基础研究将提供新的机制见解。最后，我们将探讨所生成化合物的性质。