Vectorial Cores for Fragment-based Drug-Discovery

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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.