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

Abstract

Although involved in various physiological functions, nucleoside bis-phosphate analogues and their metal-ion complexes have been scarcely studied. Hence, here, we explored the solution conformation of 2′-deoxyadenosine- and 2′-deoxyguanosine-3′,5′-bisphosphates, 3 and 4, d(pNp), as well as their Zn(2+)/Mg(2+) binding sites and binding-modes (i.e. inner- vs. outer-sphere coordination), acidity constants, stability constants of their Zn(2+)/Mg(2+) complexes, and their species distribution. Analogues 3 and 4, in solution, adopted a predominant Southern ribose conformer (ca. 84%), gg conformation around C4'-C5' and C5'-O5' bonds, and glycosidic angle in the anti-region (213-270°). (1)H- and (31)P-NMR experiments indicated that Zn(2+)/Mg(2+) ions coordinated to P5' and P3' groups of 3 and 4 but not to N7 nitrogen atom. Analogues 3 and 4 formed ca. 100-fold more stable complexes with Zn(2+)vs. Mg(2+)-ions. Complexes of 3 and 4 with Mg(2+) at physiological pH were formed in minute amounts (11% and 8%, respectively) vs. Zn(2+) complexes (46% and 44%). Stability constants of Zn(2+)/Mg(2+) complexes of analogues 3 and 4 (log KML(M) = 4.65-4.75/2.63-2.79, respectively) were similar to those of the corresponding complexes of ADP and GDP (log KML(M) = 4.72-5.10/2.95-3.16, respectively). Based on the above findings, we hypothesized that the unexpectedly low log K values of Zn(2+)-d(pNp) as compared to Zn(2+)-NDP complexes, are possibly due to formation of outer-sphere coordination in the Zn(2+)-d(pNp) complex vs. inner-sphere in the NDP-Zn(2+) complex, in addition to loss of chelation to N7 nitrogen atom in Zn(2+)-d(pNp). Indeed, explicit solvent molecular dynamics simulations of 1 and 3 for 100 ns supported this hypothesis.

Excited state dynamics of Zn–salophen complexes

“…The process is presumably initiated by coordination of the diphosphates to the Zn atom, in line with previous experimental evidence [17,19,31]. Moreover, it is conceivable that the Zn ion is coordinated by the phosphate groups of ADP and ethanol molecules, since in water a stability constant of 5 × 10 4 is reported [32].…”

Novel crown-ether–methylenediphosphonotetrathioate hybrids as Zn(ii) chelators

“…These Δδ values may imply on inner-and outer-sphere coordination for 11-Zn(II) and 7-Zn(II) complexes, respectively. 26 Unlike Zn(II) binding to 7, 9 and 11, no shift of the signals was observed upon Mg(II)-titration (Fig. S8-S13, ESI †), indicating a clear preference of MDPT-CE analogues to Zn(II).…”

Nucleoside-2′,3′/3′,5′-bis(thio)phosphate antioxidants are also capable of disassembly of amyloid beta42-Zn(ii)/Cu(ii) aggregates via Zn(ii)/Cu(ii)-chelation

“…54 Yet, recently we found that 2′-dG3′5′PO, 3, coordinates to Zn(II) via both phosphate moieties through bridging water molecules. 47 Hence, a 4O coordination sphere of 3 is more likely.…”

“…Zn(II) complexes of analogues 1 (log K M ML 4.65), and 3 (log K M ML 4.75), are 100-fold more stable than those of the corresponding complexes with Mg(II) ions. 47 Currently, there is an urgent need for biocompatible metalion chelators capable of antioxidant activity and disassembly of Aβ-aggregates as potential therapeutics for AD. The promising antioxidant activity of analogues 1-6, 46 and their demonstrated affinity to Zn(II) ions 47 and Fe(II) ions, 46 encouraged us to evaluate them as agents for the dissolution of Aβ 42 -Zn(II)/ Cu(II) aggregates targeting the identification of novel biocom- Organic & Biomolecular Chemistry Paper patible, water soluble AD therapeutics.…”

“…47 Currently, there is an urgent need for biocompatible metalion chelators capable of antioxidant activity and disassembly of Aβ-aggregates as potential therapeutics for AD. The promising antioxidant activity of analogues 1-6, 46 and their demonstrated affinity to Zn(II) ions 47 and Fe(II) ions, 46 encouraged us to evaluate them as agents for the dissolution of Aβ 42 -Zn(II)/ Cu(II) aggregates targeting the identification of novel biocom- Organic & Biomolecular Chemistry Paper patible, water soluble AD therapeutics. Therefore, here we explored the ability of nucleoside-bis(thio)phosphate analogues 1-6 to bind Cu(II)/Zn(II)-ions, the geometry and stoichiometry of these complexes as well as the Cu(II)/Zn(II)-bindingsites and binding mode.…”