New Directions in Fragment-Oriented Synthesis: Synthesis of 3D Fragment Evolution Building Blocks

Introduction
Fragment-based drug discovery (FBDD) is an established method for the identification of lead compounds in the discovery of new drugs for the treatment of a wide range of diseases.1 Fragments are relatively small, functionalised compounds with appropriate lipophilicity (mol. wt. = 140-230; non-hydrogen atoms 10-14; clogP 0-2). Current commercial and proprietary fragment libraries consist mainly of 2D, flat heteroaromatic fragments. To address this, there is growing interest in the development of novel 3D fragment libraries.2 However, one of the most limiting steps in the FBDD process is the time taken to evolve a fragment hit into a lead compound .3 This project, which brings together Unsworth’s synthetic creativity with O’Brien’s experience with 3D fragments, aims to develop a new synthetic concept for FBDD: 3D Fragment Evolution Building Blocks, which will specifically address the current limitations in fragment evolution.

Project Outline
To realise the potential of 3D fragments in FBDD, we propose a new concept which is shown schematically below. We will design and synthesise 3D fragment evolution building blocks which will be based on 3D fragments from our current research programmes. The building blocks will be structurally equivalent to the 3D fragments but equipped with functionality that will make their evolution/elaboration to lead-like compounds a straightforward process via established methods (e.g. Suzuki coupling, alkylation, reductive amination). This is a new concept that has the potential to add significant value to the 3D fragments that are being prepared in the Unsworth/O’Brien groups. New synthetic methods/approaches will be needed to prepare the 3D fragment evolution building blocks.
Training: Training in synthetic organic chemistry will be provided to ensure a strong overall knowledge of organic chemistry as well as the synthesis of small molecules and the associated practical techniques that all synthetic chemists need to master, i.e. anhydrous techniques, chromatographic purification, compound characterisation. Group meetings will allow regular opportunities to develop skills in presenting and discussing scientific ideas.
References
1. C. W. Murray and D. C. Rees Nature Chemistry 2009, 1, 187.
2. A. D. Morley et al. Drug Disc. Today 2013, 18, 1221.
3. C. W. Murray and D. C. Rees Angew. Chem. Int. Ed. 2016, 55, 488.

Shortlisted applicants will be invited for an interview to take place at the University of York on Wednesday 15 February 2017. Candidates will be asked to give a 5 minute presentation as part of their interview by an academic panel. Applicants shortlisted for interview will be notified by 1 February 2017. All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills

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