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Synthesis of water-soluble dinuclear mn-porphyrin with multiple antioxidative activities.

ABSTRACT: Superoxide dismutase (SOD) and catalase activities of a drug are of great importance for its effective protection against reactive oxygen species (ROS)-induced injury. Achievement of catalase activity of a synthetic compound remains a challenge. Water-soluble Mn-porphyrins have high SOD and peroxynitrite (ONOO(-)) reducing activities, but not catalase-like activity. Herein, we are able to retain the fair SOD-like activity of a mononuclear Mn-5-(N-methylpyridinium-4-yl)-10,15,20-triphenyl porphyrin (MnM4PyP3P), while gaining in catalase-like activity with its dinuclear complex, 1,3-di[5-(N-methylene-pyridinium-4-yl)-10,15,20-triphenyl porphynato manganese] benzene tetrachloride (MnPD). Mechanistic study indicates that catalase-like activity of MnPD is due to synergism of two Mn active sites, where hydroxo-Mn(IV) complex is formed as an intermediate. The in vivo experiments demonstrate that MnPD significantly restores the treadmill-running ability of SOD-deficient mouse and thus indicates the therapeutic potential of MnPD. Furthermore, MnPD may serve as a mechanistic tool and indicate the new directions in the synthesis of catalase-like mimics.

SUBMITTER: Kubota R

PROVIDER: S-EPMC4060938 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Synthesis of water-soluble dinuclear mn-porphyrin with multiple antioxidative activities.

Kubota Riku R Imamura Shinya S Shimizu Takahiko T Asayama Shoichiro S Kawakami Hiroyoshi H

ACS medicinal chemistry letters 20140327 6

Superoxide dismutase (SOD) and catalase activities of a drug are of great importance for its effective protection against reactive oxygen species (ROS)-induced injury. Achievement of catalase activity of a synthetic compound remains a challenge. Water-soluble Mn-porphyrins have high SOD and peroxynitrite (ONOO(-)) reducing activities, but not catalase-like activity. Herein, we are able to retain the fair SOD-like activity of a mononuclear Mn-5-(N-methylpyridinium-4-yl)-10,15,20-triphenyl porphyr ...[more]

PMID: 24944735

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Project description:Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the pKa value of the proton-acceptor site. Both high-valent transition-metal oxo M(IV)═O (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M(III)OH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn(III)OR compounds [R = (p)NO2Ph (5), Ph (6), Me (7), H (8)], some of which abstract H atoms. The Mn(III)OH complex 8 is water-soluble and represents a rare example of a stable mononuclear Mn(III)OH. In water, the redox potential of 8 was found to be pH-dependent and the Pourbaix (E(p,c) vs pH) diagram has a slope (52 mV pH(-1)) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound 7 and 8, are found to oxidize 2,2',6,6'-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated 5 and 6, are shown to be unreactive. Hydroxide-bound 8 reacts with TEMPOH an order of magnitude faster than methoxide-bound 7. Kinetic data [kH/kD = 3.1 (8); kH/kD = 2.1 (7)] are consistent with concerted H-atom abstraction. The reactive species 8 can be aerobically regenerated in H2O, and at least 10 turnovers can be achieved without significant degradation of the "catalyst". The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol(-1) for Mn(II)OH2 in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol(-1). The reduced protonated derivative of 8, [Mn(II)(S(Me2)N4(tren))(H2O)](+) (9), was estimated to have a pKa of 21.2 in MeCN. The ability (7) and inability (5 and 6) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn(II)O(H)R pKa based on their experimentally determined redox potentials. The trend in pKa [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = (p)NO2Ph)] is shown to oppose that of the oxidation potential E(p,c) [-220 (R = (p)NO2Ph) > -300 (R = Ph) > -410 (R = Me) > -600 (R = H) mV vs Fc(+/0)] for this particular series.

Dataset Information

Synthesis of water-soluble dinuclear mn-porphyrin with multiple antioxidative activities.

Publications

Synthesis of water-soluble dinuclear mn-porphyrin with multiple antioxidative activities.

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