Vectorial Cores for Fragment-based Drug-Discovery

该项目将开发新的合成方法，以构建一个矢量功能化工具箱，用于基于片段的药物设计（FBDD）的先前未合成的杂环支架。虽然FBDD已经成功地应用于许多研究，但这是使用相对有限的一组杂芳香支架实现的。尽管最近已经有相当多的努力致力于3D核心的开发，但相对而言，很少有努力用于增加杂环碎片的多样性，这些杂环碎片通常用作这些3D内部的辅助装饰。反映这一点的研究表明，虽然理论上的化疗空间在结构和物理化学性质上是多样化的，但大多数杂环结构都位于结构相似的小岛屿上，药物化学家无法探索未被占用的，因此是前所未有的区域。在这个项目中，我们建议建立在这些分析和准备以前描述的杂环系统。将此类分子用于FBDD的一个挑战是使杂环片段功能化，以实现与替代取代基建立所需的连接，这需要从头开始，并且通常具有挑战性。因此，拟议项目的一个重要方面将是为每个杂环的后期功能化开发通用的补充方法，这些方法可以以顺序和矢量多样化的方式应用。特别是，将通过硼化、氟化和金属化引入复杂性，为结合点和手柄提供正交向量，以确保将适当的物理化学剖面纳入每个结构。为了验证新的片段库，将在达勒姆和其他地方进行的化学生物学研究中分析所有化合物的目标参与。

This project will develop new synthetic methodology to enable the construction of a toolbox of vectorially functionalized, previously unsynthesised heterocyclic scaffolds for fragment-based drug design (FBDD). Whilst FBDD has been successfully applied to a number of studies this has been achieved using a relatively limited set of heteroaromatic scaffolds. Although, considerable recent effort has been directed towards the development of 3D cores, comparatively little effort has been expended to increase the diversity of heterocyclic fragments often used as auxiliary decoration for these 3D-interiors. Reflecting this, studies have shown that whilst theoretical chemotherapeutic space is diverse in terms of structure and physico-chemical properties, most heterocyclic structures are located in small islands of structural similarity with medicinal chemists being unable to explore unoccupied and therefore unprecedented regions. In this project we propose build on these analyses and prepare previously undescribed heterocyclic systems. A challenge in using such molecules for FBDD is functionalising heterocyclic fragments to enable desired connections to be established with alternative substituents requiring de novo and often challenging synthesis. Consequently, an important aspect of the proposed project will be to develop generic complementary methods for late stage functionalisation of each heterocycle that can be applied in a sequential and vectorially diverse manner. In particular ,complexity will be introduced through borylation, fluorination and metalation to provide orthogonal vectors for points of combination and handles to ensure suitable physicochemical profiles can be incorporated into each structure. To validate the new fragment library all compounds will be assayed for target engagement in ongoing chemical biology studies in Durham and elsewhere.