On the basis of the high affinity of Zn2+ to sulfur and imidazole, we targeted nucleotides such as GDP-beta-S, ADP-beta-S, and AP(3)(beta-S)A, as potential biocompatible Zn2+-chelators. The thiophosphate moiety enhanced the stability of the Zn2+-nucleotide complex by about 0.7 log units. ATP-alpha,beta-CH2-gamma-S formed the most stable Zn2+-complex studied here, log K 6.50, being similar to 0.8 and similar to 1.1 log units more stable than ATP-gamma-S-Zn2+ and ATP-Zn2+ complexes, and was the major species, 84%, under physiological pH. Guanine nucleotides Zn2+ complexes were more stable by 0.3-0.4 log units than the corresponding adenine nucleotide complexes. Likewise, AP(3)(beta-S)A-zinc complex was similar to 0.5 log units more stable than AP(3)A complex. H-1- and P-31 NMR monitored Zn2+ titration showed that Zn2+ coordinates with the purine nucleotide N7-nitrogen atom, the terminal phosphate, and the adjacent phosphate. In conclusion, replacement of a terminal phosphate by a thiophosphate group resulted in decrease of the acidity of the phosphate moiety by approximately one log unit, and increase of stability of Zn2+-complexes of the latter analogues by up to 0.7 log units. A terminal phosphorothioate contributed more to the stability of nucleotide-Zn2+ complexes than a bridging phosphorothioate.