Vectorial Cores for Fragment-based Drug-Discovery

该项目将开发新的合成方法，以构建矢量功能化的工具箱，以前未合成的杂环支架用于基于片段的药物设计（FBDD）。虽然FBDD已成功应用于许多研究，但这是使用相对有限的杂芳族支架来实现的。虽然，相当多的最近的努力已经指向3D核心的发展，相对较少的努力已经花费，以增加杂环片段的多样性，通常用作这些3D内部的辅助装饰。反映这一点，研究表明，虽然理论上的化疗空间在结构和物理化学性质方面是多样的，但大多数杂环结构位于结构相似的小岛上，药物化学家无法探索未被占据的区域，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制备以前未描述的杂环系统。将此类分子用于FBDD的挑战是使杂环片段官能化以使得能够与需要从头合成且通常具有挑战性的替代取代基建立所需连接。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的方式应用。特别是，复杂性将通过硼基化，双金属化和金属化来引入，以提供组合点和手柄的正交矢量，以确保合适的物理化学特征可以并入每个结构中。为了验证新的片段文库，将在达勒姆和其他地方进行的化学生物学研究中测定所有化合物的靶向结合。

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.