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Design and synthesis of medium-ring compounds to target nucleotide binding sites

Stuart Rankin

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Wellcome Trust (WT)
Hypothesis That compounds based on a medium ring scaffold incorporating a ribose mimic can be potent and selective inhibitors of nucleotide-dependent enzymes. Aims The aim of the project is to synthesise a library of compounds based on a 9-membered medium ring core and screen them for inhibition of the HSP70 protein family. The major points of variation for the library will be the 3-position ether (R1) and at the 7-position (R2). As shown by comparison with ATP and modelling within the active site of HSP70, the R1 substituents will primarily mimic the adenine portion of ATP while the R2 substituents will mimic the triphosphate region of a nucleotide.

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