Synthesis of pyrrothiamine, a novel thiamine analogue, and evaluation of derivatives as potent and selective inhibitors of pyruvate dehydrogenase

Inhibition of thiamine pyrophosphate (TPP)-dependent enzymes with thiamine/TPP analogues that have the central thiazolium ring replaced with other rings is well established, but a limited number of central rings have been reported. We report a novel analogue, pyrrothiamine, with a central pyrrole ring. We further develop pyrrothiamine derivatives as potent and selective inhibitors of pyruvate dehydrogenase, which might have anti-cancer potential. Pyrrothiamine, a new thiamine analogue with the S replaced by CH, has been synthesised and is a moderate inhibitor of a range of thiamine pyrophosphate-dependent enzymes. Its ester 19 is a potent and selective inhibitor of pyruvate dehydrogenase.