Characterization of Complexes of Nucleoside-5′-Phosphorothioate Analogues with Zinc Ions

Abstract

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.

Adenosine/guanosine-3′,5′-bis-phosphates as biocompatible and selective Zn2+-ion chelators. Characterization and comparison with adenosine/guanosine-5′-di-phosphate

“…Ap 3 (β-S)A, 7-Zn 2+ (log K = 5.74/6.5 vs. 3.8, respectively). 15 Subsequently, we reported that an additional terminal phosphate group on the AMP/GMP scaffold, as in 2′-deoxy-adenosine/guanosine-3′,5′-bisphosphate, resulted in a 1.8-and 2.8-fold increased Fe 2+ chelation as compared to adenosine/guanosine-5′-monophosphate, respectively. 16 Hence, we hypothesized that enhanced Fe 2+ or Zn 2+ chelation is due to the presence of two terminal phosphate groups in d(pNp) vs. one terminal phosphate group in NMP analogues, 16 or one terminal phosphate in ATP vs. no terminal phosphate in Ap 3 A.…”

Identification of adenine-N9-(methoxy)ethyl-β-bisphosphonate as NPP1 inhibitor attenuates NPPase activity in human osteoarthritic chondrocytes

“…Analog 7, although more potent than 6, showed less selectivity for NPP1. Analog 6 (at 100 μM) only slightly inhibited NPP3, NTPDase1, and NTPDase3 (38, 0, 22%) [13,44].…”

ATP-γ-S-(α,β-CH2) protects against oxidative stress and amyloid beta toxicity in neuronal culture

“…Recently, we have reported the ability of ATP-g-S-(a,b-CH 2 ) to dissolve Ab 40 -Cu(I) and Ab 42 -Cu(II)/Zn(II) aggregates, much more effectively than ATP-g-S, ATP, or EDTA [10]. We have also determined its high affinity to Zn(II)-ions [16]. Hence, we assume that the ability of ATP-g-S-(a,b-CH 2 ) to dissolve Ab-M(II) aggregates, and consequently rescue neurons from Ab toxicity, results from metal-ions chelation.…”

“…The highly promising properties of ATP-g-S-(a,b-CH 2 ) as a Fenton reaction inhibitor [10], an effective ion chelator [16], a powerful agent for in-vitro dissolution of Ab 40/42 -M(II) oligomers and aggregates [10], together with its enzymatic stability, and its high activity at P2Y11-R [12], encouraged us to explore the potential of ATP-g-S-(a,b-CH 2 ) for the rescue of primary neurons subjected to insults typical of Alzheimer's disease.…”