A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties

Superoxide, a potentially toxic by-product of cellular metabolism, may contribute to tissue injury in many types of human disease. Here we show that a tris-malonic acid derivative of the fullerene C-60 inolecule (C-3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C-3 and superoxide was not via stoichiometric scavenging, as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C-3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism. A model is proposed in which electron-deficient regions on the C-60 sphere work in concert with malonyl groups attached to C-3 to electrostatically guide and stabilize Superoxide, promoting dismutation. We also found that C-3 treatment of Sod2(-/-) mice. which lack expression of mitochondrial manganese superoxide dimutase (MnSOD), increased their life span by 300%. These data, coupled with evidence that C-3 localizes to mitochondria, suggest that C-3 functionally replaces MnSOD, acting as a biologically effective SOD mimetic. (C) 2004 Elsevier Inc. All rights reserved.