Oligonucleotides are potent antioxidants acting mainly as metal-ion chelators.

We explored by ESR the potential of 2'-deoxy-oligonucleotides as biocompatible inhibitors of the Fe(II)/Cu(I)/(II)-induced *OH formation from H(2)O(2). d(A)(5), (2'-OMe-A)(5), d(A)(7), d(A)(20), and d(T)(20), proved highly potent antioxidants (IC(50): 5-17 or 48-85 microM in inhibiting Fe(II)/Cu(I)- or Cu(II)-induced H(2)O(2)- decomposition), representing 40 to 215 - fold increase of potency as compared to Trolox. The antioxidant activity does not depend on the oligonucleotides' length or composition. The primary inhibition mechanism by oligonucleotides is metal-ion chelation and the secondary is radical scavenging. (1)H-, (31)P-NMR and ESR data suggest that Cu coordination involves adenine bases and 1-2 phosphates. We propose the use of short, metabolically stable oligonucleotides as highly potent and long-lived (t(1/2) ca. 20 h) antioxidants that may prevent oxidative damage.