Nucleoside—2′,3′/3′,5′-Bis(thio)phosphate Analogues Are Promising Antioxidants Acting Mainly via Cu⁺/Fe²⁺ Ion Chelation

Abstract

We synthesized a series of adenine/guanine 2',3'- or 3',5'-bisphosphate and -bisphosphorothioate analogues, 1-6, as potential Cu(+)/Fe(2+) chelators, with a view to apply them as biocompatible and water-soluble antioxidants. We found that electron paramagnetic resonance (EPR)-monitored inhibition of OH radicals production from H2O2, in an Fe(2+)-H2O2 system, by bisphosphate derivatives 1, 3, and 5 (IC50 = 36, 24, and 40 μM, respectively), was more effective than it was by ethylenediaminetetraacetic acid (EDTA), by a factor of 1.5, 2, and 1.4, respectively. Moreover, 2'-deoxyadenosine-3',5'-bisphosphate, 1, was 1.8- and 4.7-times more potent than adenosine 5'-monophosphate (AMP) and adenosine 5'-diphosphate (ADP), respectively. The bisphosphorothioate derivatives 2, 4, and 6 (IC50 = 92, 50, and 80 μM, respectively), exhibited a dual antioxidant activity, acting as both metal-ion chelators and radical scavengers [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay data indicates IC50 = 50, 70, and 108 μM vs 27 μM for Trolox]. Only 2'-deoxyadenosine-3',5'-bisphosphorothioate, 2, exhibited good inhibition of Cu(+)-induced H2O2 decomposition (IC50 = 78 vs 224 μM for EDTA). Nucleoside-bisphosphorothioate analogues (2, 4, and 6) were weaker inhibitors than the corresponding bisphosphate analogues (1, 3, and 5), due to intramolecular oxidation under Fenton reaction conditions. (1)H- and (31)P NMR monitored Cu(+) titration of 2, showed that Cu(+) was coordinated by both 3',5'-bisphosphorothioate groups, as well as N7-nitrogen atom, while adenosine-2',3'-bisphosphorothioate, 6, coordinated Cu(+) only by 2',3'-bisphosphorothioate groups. In conclusion, an additional terminal phosphate group on AMP/guanosine 5'-monophosphate (GMP) resulted in Fe(2+)-selective chelators highly potent as Fenton reaction inhibitors.

Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential

“…two O-to-S substitutions each positioned within two neighbouring phosphate moieties. While there are numerous reported syntheses of nucleotide analogs containing a single O-to-S substitution within the oligophosphate bridge (19,38–41), synthesis and properties of compounds containing two neighbouring O-to-S substitutions have hardly been described. Ludwig and Eckstein achieved the synthesis and purification of guanosine 5′-O-(1,2-dithiotriphosphates) (GTPαSβS) diastereomers via chemoenzymatic method and studied their interaction with Cd 2+ ions.…”

The Mechanism of Melanocytes-Specific Cytotoxicity Induced by Phenol Compounds Having a Prooxidant Effect, relating to the Appearance of Leukoderma

“…Further, proteins containing copper are known to enhance oxidation reactions and induce apoptosis [ 6 , 7 ]. Moreover, a metal chelating agent such as disodium dihydrogen ethylenediaminetetraacetate dehydrate (EDTA) inhibits the oxidation reaction of transition metals such as iron and copper with hydrogen peroxide (H 2 O 2 ), which induces Fenton reaction [ 8 , 9 ].…”

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

“…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. 15 Based on these findings we expected that two terminal phosphate groups, as in nucleoside bis-phosphate analogues 3 and 4, will increase the log K values of their M 2+ complexes as compared to the corresponding nucleoside 5′-di-phosphate (1 and 2) complexes.…”