文摘
We synthesized a series of adenine/guanine 2鈥?3鈥? or 3鈥?5鈥?bisphosphate and -bisphosphorothioate analogues, 1鈥?b>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 渭M, respectively), was more effective than it was by ethylenediaminetetraacetic acid (EDTA), by a factor of 1.5, 2, and 1.4, respectively. Moreover, 2鈥?deoxyadenosine-3鈥?5鈥?bisphosphate, 1, was 1.8- and 4.7-times more potent than adenosine 5鈥?monophosphate (AMP) and adenosine 5鈥?diphosphate (ADP), respectively. The bisphosphorothioate derivatives 2, 4, and 6 (IC50 = 92, 50, and 80 渭M, respectively), exhibited a dual antioxidant activity, acting as both metal-ion chelators and radical scavengers [2,2鈥?azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay data indicates IC50 = 50, 70, and 108 渭M vs 27 渭M for Trolox]. Only 2鈥?deoxyadenosine-3鈥?5鈥?bisphosphorothioate, 2, exhibited good inhibition of Cu+-induced H2O2 decomposition (IC50 = 78 vs 224 渭M for EDTA). Nucleoside鈥揵isphosphorothioate 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鈥?5鈥?bisphosphorothioate groups, as well as N7-nitrogen atom, while adenosine-2鈥?3鈥?bisphosphorothioate, 6, coordinated Cu+ only by 2鈥?3鈥?bisphosphorothioate groups. In conclusion, an additional terminal phosphate group on AMP/guanosine 5鈥?monophosphate (GMP) resulted in Fe2+-selective chelators highly potent as Fenton reaction inhibitors.
