Synthesis, modeling and evaluation of 3'-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3'-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors.
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 TK2 versus TK1. Interestingly, for the current series of analogues, a strong correlation was observed between TK2 and Drosophila melanogaster dNK inhibition, further substantiating the phylogenetic relationship between these two nucleoside kinases.
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, B-90000, Gent, Belgium. serge.vancalenbergh@ugent.be
Sara
S
Van Poecke
Ana
A
Negri
Jolien
J
Janssens
Nicola
N
Solaroli
Anna
A
Karlsson
Federico
F
Gago
Jan
J
Balzarini
Serge
S
Van Calenbergh
D000588:Amines / Q000737:chemistry*; D000818:Animals; D001393:Azoles / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013936:Thymidine / Q000138:chemical synthesis* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000588:Amines; D001393:Azoles; C105339:thymidine kinase 2; D013937:Thymidine Kinase; D013936:Thymidine