Exploring the functionalisation of the thieno[2,3-d]pyrimidinedione core: Late stage access to highly substituted 5-carboxamide-6-aryl scaffolds

Kerry M O'Rourke,Erin S Johnstone,Holger M Becker,Sally L Pimlott,Andrew Sutherland

doi:10.1016/j.tet.2018.06.019

Kerry M O'Rourke, Erin S Johnstone + Show 3 more

Open Access

https://doi.org/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.

Highlights

Due to their similarity in structure to nucleic acid bases, pyrrolo [2,3-d]pyrimidine and thieno[2,3-d]pyrimidine scaffolds display a wide range of biological activities [1]
The morpholine carboxamides showed a slight inhibitory effect on MCT4, with compounds 14 and 16 showing ~10% reduction in uptake. These compounds are not significantly active in inhibiting lactate uptake, this study has demonstrated the structure activity relationship of this series and identified thieno[2,3-d]pyrimidinedione morpholine carboxamide derivatives as potential scaffolds for further development as lactate uptake inhibitors of monocarboxylate transporters (MCT)
A reliable and scalable route for the synthesis of a thieno[2,3-d]pyrimidinedione core bearing a C-5 ester moiety has been achieved from a mercaptouracil derivative by an alkylation reaction with ethyl 3-bromopyruvate followed by an acid-mediated cyclisation

Summary

Introduction

Due to their similarity in structure to nucleic acid bases, pyrrolo [2,3-d]pyrimidine and thieno[2,3-d]pyrimidine scaffolds display a wide range of biological activities [1]. Within this structural class, the thieno[2,3-d]pyrimidinediones have been of particular interest, with pharmaceutical activity against a wide range of disease states. We have determined various physicochemical properties of these compounds, highlighting the potential of this scaffold for medicinal chemistry applications. The ability of these novel thieno[2,3-d]pyrimidinedione-5-carboxamide-6-aryl analogues to inhibit lactate uptake of monocarboxylate transporters 1, 2 and 4 in Xenopus oocytes is presented

Results and discussion

Conclusions

General methods

Experimental procedures and compound characterisation

Biological assay for the inhibition of lactate uptake in Xenopus oocytes