Nucleoside - 2′,3′/3′,5′-bis(thio)phosphate analogues are promising antioxidants acting mainly via Cu+/Fe 2+ ion chelation

Bosmat Levi Hevroni, Alon Haim Sayer, Eliav Blum, Bilha Fischer

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9 Scopus citations


We synthesized a series of adenine/guanine 2′,3′- or 3′,5′-bisphosphate and -bisphosphorothioate analogues, 1-6, as potential Cu+/Fe2+ 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 Fe2+-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 IC 50 = 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. 1H- and 31P 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 Fe2+-selective chelators highly potent as Fenton reaction inhibitors.

Original languageEnglish
Pages (from-to)1594-1605
Number of pages12
JournalInorganic Chemistry
Issue number3
StatePublished - 3 Feb 2014


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