The Ortho Effect Makes Manganese(III)Meso-Tetrakis(N-Methylpyridinium-2-yl)Porphyrin a Powerful and Potentially Useful Superoxide Dismutase Mimic

Abstract

The ortho, meta, and para isomers of manganese(III) 5,10,15,20-tetrakis(N-methylpyridyl)porphyrin, MnTM-2-PyP 5؉ , MnTM-3-PyP 5؉, and MnTM-4-PyP 5؉ , respectively, were analyzed in terms of their superoxide dismutase (SOD) activity in vitro and in vivo. The impact of their interaction with DNA and RNA on the SOD activity in vivo and in vitro has also been analyzed. Differences in their behavior are due to the combined steric and electrostatic factors. In vitro catalytic activities are closely related to their redox potentials. The half-wave potentials (E1 ⁄2 ) are ؉0.220 mV, ؉0.052 mV, and ؉0.060 V versus normal hydrogen electrode, whereas the rates of dismutation (k cat ) are 6.0 ؋ 10 7 , 4.1 ؋ 10 6 , and 3.8 ؋ 10 6 M ؊1 s ؊1 for the ortho, meta, and para isomers, respectively. However, the in vitro activity is not a sufficient predictor of in vivo efficacy. The ortho and meta isomers, although of significantly different in vitro SOD activities, have fairly close in vivo SOD efficacy due to their similarly weak interactions with DNA. In contrast, due to a higher degree of interaction with DNA, the para isomer inhibited growth of SOD-deficient Escherichia coli.Due to their high stability and chemical versatility, manganese porphyrins are a promising group of compounds for development as SOD 1 mimics. Introducing ␤-electron-withdrawing substituents and modifying meso substituents of water soluble porphyrins can have a major impact on the redox and electrostatic properties of manganese porphyrins (1-7). Such substitution allows the redox potential to approach the potential of SOD itself, E1 ⁄2 ϳ ϩ0.26 V (8). This is approximately midway between the redox potentials of the two half-reactions of the dismutation process (9, 10). While maintaining the redox potential at a value close to that of SOD, it is important to also ensure electrostatic facilitation. We have already shown that ␤-bromination (11, 12) of the manganese(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin (13) and of manganese(III) 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin increases their SOD-like activities (13).2 However, the large positive redox potential of the former, E1 ⁄2 ϭ ϩ0.480 mV versus NHE, (13) stabilizes manganese in its 2ϩ state and diminishes stability, and the latter compound had only modest activity, probably due to lack of electrostatic facilitation (13).It has been shown that ortho substitution on the meso phenyl ring exhibits an ortho effect that is as strong as if the same substituent were placed directly on the meso position (14). Thus, meso-tetrakis(2-methylphenyl)porphyrin behaves similar to the meso tetramethylporphyrin (14). The same was found for other porphyrins in which meso phenyl groups have different ortho substituents, as well as when meso groups are ortho pyridyls, such as 5,10,15,20-tetrakis-(N-methylpyridinium-2-yl) (H 2 TM-2-PyP 4ϩ ) and its zinc complex, ZnTMP-2-PyP 4ϩ (15)(16)(17)(18)(19). Such a profound impact on the properties of the ortho isomers, known as the ortho effect, is due to the combi...

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

“…Mn III TM-2-PyP 5+ (chloride salt) [26] and Mn III TM-3-PyP 5+ (chloride salt) [26] were prepared and characterized as previously described.…”

“…A 2-fold excess of MnCl 2 ·4H 2 O (10.5 mg, 0.0528 mmol) was added followed by a drop in pH from 11.2 to ~9 along with instantaneous color change from reddish pink to green. Metathesis of the anions of this Mn porphyrin with NH 4 PF 6 to yield the PF 6 [26], the pH dropped too much (to ~6.5), due to the extensive hydrolysis of Mn, and prevented a completion of metallation.…”

“…Our first report on a potent ortho isomer, Mn III TM-2-PyP 5+ , in protecting SOD-deficient E. coli indicated that the meta isomer, Mn III TM-3-PyP 5+ , although ~10-fold inferior with respect to in vitro antioxidant potency [1] may still be effective in vivo [26]. Indeed, meta isomer was comparable to the ortho analogue in providing protection to SOD-deficient E. coli to grow aerobically in restricted five amino acid-medium while para isomer, MnTM-4-PyP 5+ , was toxic [26].…”

“…Indeed, meta isomer was comparable to the ortho analogue in providing protection to SOD-deficient E. coli to grow aerobically in restricted five amino acid-medium while para isomer, MnTM-4-PyP 5+ , was toxic [26]. The reason likely lies in lesser bulkiness of the meta isomer, which allows it to accumulate within E. coli at higher levels than the ortho analogue [26]. Para isomer was toxic due to its interactions with nucleic acids [26].…”

“…The reason likely lies in lesser bulkiness of the meta isomer, which allows it to accumulate within E. coli at higher levels than the ortho analogue [26]. Para isomer was toxic due to its interactions with nucleic acids [26]. Guided by these collective in vitro, in vivo, and SAR results [1][2][3][4][5]12,[24][25][26], we resumed herein our studies on the meta Mn(III) Nalkylpyridylporphyrins by preparing a brominated derivative of Mn III TM-3-PyP 5+ .…”