O'Rourke, K., Johnstone, E. S., Becker, H. M., Pimlott, S. L. and Sutherland, A. (2018) Exploring the functionalisation of the thieno[2,3-d]pyrimidinedione core: late stage access to highly substituted 5-carboxamide-6-aryl scaffolds. Tetrahedron, 74(30), pp. 4086-4094. (doi: 10.1016/j.tet.2018.06.019)
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Abstract
The thieno[2,3-d]pyrimidinedione core is found as a component in a range of pharmaceutically active compounds, however, synthetic approaches to these scaffolds rely on access to functionalised, highly substituted thiophenes. Here we describe a new approach for the preparation of 5-carboxamide-6-aryl analogues that involves a two-step synthesis of the thieno[2,3-d]pyrimidinedione core from a readily available mercaptouracil derivative. Thio-alkylation with ethyl 3-bromopyruvate, followed by cyclisation and dehydration mediated by polyphosphoric acid allowed the scalable synthesis of the thieno[2,3-d] pyrimidinedione unit. The late-stage functionalisation of this core motif via bromination of the thiophene ring and a subsequent Suzuki-Miyaura reaction as the key steps permitted access to a novel library of 5-carboxamide-6-aryl analogues. The physicochemical properties of these compounds were determined, generating an insight into the potential bioavailability of these scaffolds. Based on these results, a selection of the novel 5-carboxamide-6-aryl analogues were tested as lactate uptake inhibitors of monocarboxylate transporters 1, 2 and 4 in Xenopus oocytes.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Pimlott, Dr Sally and O'Rourke, Kerry and Sutherland, Professor Andrew |
| Authors: | O'Rourke, K., Johnstone, E. S., Becker, H. M., Pimlott, S. L., and Sutherland, A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing College of Science and Engineering > School of Chemistry |
| Journal Name: | Tetrahedron |
| Publisher: | Elsevier |
| ISSN: | 0040-4020 |
| ISSN (Online): | 1464-5416 |
| Published Online: | 12 June 2018 |
| Copyright Holders: | Copyright © 2018 The Authors |
| First Published: | First published in Tetrahedron 74(30):4086-4094 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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