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.

在药物化学中纳入“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的新领域的机会。这对于能够提供改进的物理化学性质或新的替代基团的基团特别有吸引力。在这种背景下，氮杂硫 (VI) 基序（包含 S=N 基团）的出现，提供了有吸引力的性能平衡和受控的三维框架，并充当其他重要功能的生物等排体。这一点在亚砜亚胺中最为显着，它在阿斯利康的 ATR 抑制剂 AZD6738 (Ceralasertib) 中发挥着重要作用，用于各种晚期癌症的临床试验。该项目将开发新的立体控制方法来生成氮杂硫 (VI) 基序，预计将为药物化学提供有价值的设计选择。我们将开发一些方法，让人们更容易地获得这些尚未充分探索的基序，并控制绝对的 3D 形状，使药物化学家能够轻松地将它们纳入发现计划中。将为亚磺酰亚胺、磺酰亚胺和磺二亚胺基团开发新的立体控制工艺。此外，还将开发各个氮原子的官能化，以证明整体性质的可调性以及环状衍生物的制备。该项目符合 EPSRC 医疗保健转型的优先事项。我们将开发用于药物和化学探针的新替代基团的便捷获取方式，并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 键形成来不对称合成目标结构，以最大程度地灵活地将这些衍生物纳入药物发现计划，并直接获得硫原子上的任一构型。对这些过程中中间体的基础研究将提供新的机制见解。最后我们将探索生成的化合物的特性。