Novel ribofuranosylnucleoside lead compounds for potent and selective inhibitors of mitochondrial thymidine kinase-2

The ribonucleoside analogues (E)-5-(2-bromovinyl)uridine (5-BV-Urd) and 3´-spiro-(4´-amino-1´,2´-oxathiole-2´,2´-dioxide)-5-methyluridine (3´-AOD-5-MeUrd) emerged as potent and selective competitive inhibitors of mitochondrial thymidine kinase (TK)-2 with respect to thymidine (Ki/Km values of 9.0 and 1.2 respectively). Cytosolic TK-1 did not show measurable affinity for these compounds. [32P]Phosphate transfer studies from [γ-32P]ATP to 5-BV-Urd and 3´-AOD-5-MeUrd revealed extremely poor substrate activity but potent inhibitory potential of the compounds. It was concluded that the ribonucleosides 5-BV-Urd and 3´-AOD-5-MeUrd represent two new lead compounds for potent and selective inhibitors of mitochondrial TK-2.