The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non-proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron.In biology, iron and manganese play important roles in oxygen chemistry. Both metals are used in oxygen evolution through photosynthesis and can also serve as cofactors for enzymes that remove harmful byproducts of O 2 metabolism such as superoxide (O 2 . ) and hydrogen peroxide, yet a major difference lies in the propensity of these metals to cause oxidative damage. Iron is well known for its reactivity with peroxide, generating the highly reactive hydroxyl radical through so-called Fenton chemistry. Manganese is less prone to such chemistry due to a higher reduction potential. Iron is often considered a pro-oxidant in biology under situations in which manganese is an antioxidant. Without the deleterious side effects of Fenton chemistry, manganese can safely operate as a cofactor for superoxide dismutase (SOD) 2 enzymes and also provide oxidative stress resistance through formation of nonproteinaceous manganese-based antioxidants. Herein, we focus on these two biological roles of manganese in oxidative stress protection and the potential challenges faced by competing pools of iron. Manganese Versus Iron as Cofactors for SODSOD enzymes fall into three distinct families that are unrelated in sequence but have converged in evolution to utilize a redox-active metal to disproportionate O 2 . into hydrogen peroxide and oxygen. These families are classified according to metal cofactor and include Cu,Zn-SODs, which use copper for catalysis and also bind a structural zinc atom; a rarer family of nickel-containing SODs (1); and an extensive Mn/Fe-SOD family that uses either manganese or iron. Members of the Mn/Fe-SOD family are widespread in biology and are thought to have evolved from a common ancestor prior to the divergence of eubacteria, archaebacteria, and eukaryotes over 3 billion years ago (2, 3). The active sites of Mnand Fe-SODs are virtually indistinguishable. The manganese or iron cofactor is coordinated to three histidines, one aspartate, and one solvent molecule in a distorted trigonal bipyramidal geometry. Outside the active site, the overall primary sequence and tertiary folds of Mn-and Fe-SODs are remarkably similar. Despite this striking conservation, these SODs are exquisitely metal-specific; for example, a Mn-SOD is active only with manganese and not iron. Rare exceptions include so-called ...

The promising antitumor activity of dirhodium complexes has been known for over 30 years. There remains, however, a general lack of understanding of their activity in cellulo. In this study, we report the DNA interactions and activity in living cells of six monosubstituted dirhodium(II,II) complexes of general formula [Rh(2)(mu-O(2)CCH(3))(2)(eta(1)-O(2)CCH(3))(L)(CH(3)OH)](+), where L = bpy (2,2'-bipyridine) (1), phen (1,10-phenanthroline) (2), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline) (3), dppz (dipyrido[3,2-a:2',3'-c]phenazine) (4), dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) (5), and dap (4,7-dihydrodibenzo[de,gh][1,10]phenanthroline) (6). DNA interactions were investigated by UV/visible spectroscopy, relative viscosity measurements, and electrophoretic mobility shift assay. These measurements indicate that compound 5 exhibits the strongest interaction with DNA. Compound 5 also causes the most damage to DNA after cellular internalization, as evaluated by the alkaline comet assay. Compound 5, however, is not the most effective at inhibiting cell viability of the human cancer cells HeLa and COLO-316. The greater hydrophobicity of 5 as compared to that of 4, which is the most effective compound in the series, hinders its ability to reach its cellular target(s). Data from modulation studies of glutathione using N-acetylcysteine and L-buthionine-sulfoximine indicate that changes in glutathione levels do not affect the activity of these particular dirhodium complexes. These results suggest that glutathione is not the only agent involved in the deactivation of these dirhodium complexes.

In the series Rh2(O2CR)4 (R=CH3, 1; R=CF3, 2), [Rh2(O2CR)2(phen)2]2+ (R=CH3, 3; R=CF3, 4), and [Rh2(O2CR)2(dppz)2]2+ (R=CH3, 5; R=CF3, 6), 2, 4, and 6 are twice as cytotoxic as 1, 3, and 5, respectively. The substitution reactions of 2 with 9-ethylguanine at various temperatures take place at faster rates than those of 1, and the activation energy Ea(1)=69+/-4 kJ/mol is twice Ea(2)=35+/-2 kJ/mol. The higher cytotoxicities of [Rh2(micro-O2CCH3)2(eta1-O2CCH3)L(MeOH)]+ (L=dppz, 7; L=dppn, 8) relative to [Rh2(micro-O2CCH3)2(bpy)L]2+ (L=dppz, 10; L=dppn, 11) are attributed to the labile equatorial groups in 7 and 8 not present in 10 and 11. The toxicities of complexes 1-8 are not related to their charge or the ease by which they transverse the cellular membrane but to the lability of the ligands on the dirhodium core.