Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential

Abstract

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.

FIG. 1.

SOD mimics. Mn(III) porphyrins, Mn(II) cyclic polyamines, Mn(III) salen derivatives, nitroxides, and fullerenes were shown to possess SOD-like activity. “Free” Mn (i.e., low-molecular-weight Mn(II) species) such as aqua, oxo, hydroxo, and carboxylato species are able to dismute O₂^·− also. 5,10,15,20: meso positions of methine bridges between pyrrolic rings.

FIG. 2.

The O₂^·− dismutation process.

FIG. 3.

Redox diagram for O₂^·− reduction and oxidation and the placement of Mn porphyrins on it.

FIG. 4.

Struture-activity relationships. (A) The very first structure–activity relationship between log k_cat (O₂^·−) and E_1/2 (Mn^IIIP/Mn^IIP) included porphyrins of different charge, different stericity, and different electrostatics for O₂^·− dismutation. (B) As the E_1/2 increases, the Mn⁺² oxidation state gets stabilized, and eventually oxidation of porphyrin becomes the rate-limiting step, and k_cat starts to decrease again. Only water-soluble Mn(III) porphyrins are given in the left, linear section of the curve that obeys the Marcus equation, and data (circles) are from ref. : (1) Mn^IIITCPP³⁻, (2) Mn^IIIT(TMAP)⁵⁺, (3) Mn^IIIT(2,6-F₂-3-SO₃-P)P³⁻, (4) Mn^IIIT(TFTMAP)P⁵⁺, (5) Mn^IIIT(2,6-Cl₂-3-SO₃-P)P³⁻, (6) Mn^IIIBM-2-PyP³⁺, (7) Mn^IIITM-3-PyP⁵⁺, (8) Mn^IIITM-4-PyP⁵⁺, (9) Mn^IIITrM-2-PyP⁴⁺, (10) Mn^IIITM-2-PyP⁵⁺, and (11) Mn^IIITE-2-PyP⁵⁺. Data for EUK-8 are from ref. , and for MnCl₂, from refs. and ; data for Mn(II) cyclic polyamine M40403 are from ref. . Data for SOD are from ref. . Data for Mn^IIICl_1-4MnTE-2-PyP⁵⁺ (12–15) are from ref. , data for Mn^IIBr₈TM-4-PyP⁴⁺ (16) are from ref. , and for Mn^IICl₅TE-2-PyP⁴⁺ (#17), from ref. (triangles). Data for Mn^IIITnBu-2-PyP⁵⁺ (a) are from ref. ; Mn^IIITMOE-2-PyP⁵⁺ (b) from ref. ; Mn^IIITD(M)E-2-ImP⁵⁺ (c, d) from refs. and ; Mn^IIITM,MOE-2-PyP⁵⁺ (e), and for Mn^IIITDMOE-2-ImP⁵⁺ (f ) from ref. (squares). Data points 18 and 19 (diamonds) belong to MnTTEG-2-PyP⁵⁺ and MnTDTEG-2-ImP⁵⁺ and are from ref. .

FIG. 5.

The effect of charges on k_cat (O₂^.−). Mono- vs. pentacationic porphyrins differ in k_cat for 2 log units, whereas cationic vs. anionic porphyrins differ in k_cat for more than two orders of magnitude (A), like imidazolium vs. pyrazoliumporphyrins (B).

FIG. 6.

Structure–activity relations between log k_cat (O₂^·−) and E_1/2 (Mn^IIIP/Mn^IIP) for porphyrins that have negative charges (lower curve), no charges (middle curve), and positive charges on the periphery (upper curve).

FIG. 7.

Higher lipophilicity of meta Mn(III) N-alkylpyridylporphyrins drives their higher accumulation inside E. coli and compensates for lower antioxidant potency when compared with ortho analogues. Consequently, meta and ortho isomers are similarly efficacious in protecting SOD-deficient E. coli that lacks cytosolic SOD (178). Here, the most obvious case with ortho and meta N-ethylpyridylporpyrin is illustrated: meta isomer is ∼10-fold less SOD-active than the ortho species, but is ∼10-fold more lipophilic and accumulates ∼10-fold more in E. coli. In turn, both compounds are equally efficient in substituting for cytosolic superoxide dismutases.

FIG. 8.

Mn(III) 5,10,15 tris(N-methylpyridinium-2-yl)corrole and Gd(III) texaphyrin.

FIG. 9.

Mn(II) cyclic polyamines: the SOD-active M40403 (2S,21S nonmethylated analogue) and SOD inactive M40404 (2R,21R dimethyl derivative).