Based on the presumed binding mode of an earlier identified inhibitor, we herein report new 3′-modified nucleosides as potent and selective inhibitors of mitochondrial thymidine kinase (TK2). A series of thirteen 3′-amino-, 3′-guanidino- and 3′-tetrazole-containing nucleosides were synthesized and evaluated for their TK2 inhibitory activity. Within the tetrazole series, compounds with nanomolar inhibitory activity were identified. A homology model of TK2 allowed to elucidate the observed activities. Introduction of a 2-bromovinyl group on C-5 of the pyrimidine base of the most promising 3′-derivative further improved the inhibitory activity, and caused a significant increase in the selectivity for TK2versusTK1. Interestingly, for the current series of analogues, a strong correlation was observed between TK2 and Drosophila melanogasterdNK inhibition, further substantiating the phylogenetic relationship between these two nucleoside kinases.
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