Characterization of complexes of nucleoside-5'-phosphorothioate analogues with zinc ions.
On the basis of the high affinity of Zn(2+) to sulfur and imidazole, we targeted nucleotides such as GDP-β-S, ADP-β-S, and AP3(β-S)A, as potential biocompatible Zn(2+)-chelators. The thiophosphate moiety enhanced the stability of the Zn(2+)-nucleotide complex by about 0.7 log units. ATP-α,β-CH2-γ-S formed the most stable Zn(2+)-complex studied here, log K 6.50, being ~0.8 and ~1.1 log units more stable than ATP-γ-S-Zn(2+) and ATP-Zn(2+) complexes, and was the major species, 84%, under physiological pH. Guanine nucleotides Zn(2+) complexes were more stable by 0.3-0.4 log units than the corresponding adenine nucleotide complexes. Likewise, AP3(β-S)A-zinc complex was ~0.5 log units more stable than AP3A complex. (1)H- and (31)P NMR monitored Zn(2+) titration showed that Zn(2+) 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 Zn(2+)-complexes of the latter analogues by up to 0.7 log units. A terminal phosphorothioate contributed more to the stability of nucleotide-Zn(2+) complexes than a bridging phosphorothioate.
Department of Chemistry, Bar Ilan University , Ramat-Gan 52900, Israel.
Alon Haim
AH
Sayer
Yehudit
Y
Itzhakov
Noa
N
Stern
Yael
Y
Nadel
Bilha
B
Fischer
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D013873:Thionucleotides / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D002614:Chelating Agents; D056831:Coordination Complexes; D009705:Nucleosides; D013873:Thionucleotides; C014308:adenosine 5'-phosphorothioate; D000249:Adenosine Monophosphate; D015032:Zinc