Gilson DeFreitas-Silva

Lipophilicity of potent porphyrin-based antioxidants: Comparison of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins

Mn(III) N-alkylpyridylporphyrins are among the most potent known SOD mimics and catalytic peroxynitrite scavengers and modulators of redox-based cellular transcriptional activity. In addition to their intrinsic antioxidant capacity, bioavailability plays a major role in their in vivo efficacy. Although of identical antioxidant capacity, lipophilic MnTnHex-2-PyP is up to 120-fold more efficient in reducing oxidative stress injuries than hydrophilic MnTE-2-PyP. Owing to limitations of an analytical nature, porphyrin lipophilicity has been often estimated by the thin-layer chromatographic R(f) parameter, instead of the standard n-octanol/water partition coefficient, P(OW). Herein we used a new methodological approach to finally describe the MnP lipophilicity, using the conventional log P(OW) means, for a series of biologically active ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins. Three new porphyrins (MnTnBu-3-PyP, MnTnHex-3-PyP, and MnTnHep-2-PyP) were synthesized to strengthen the conclusions. The log P(OW) was linearly related to R(f) and to the number of carbons in the alkyl chain (n(C)) for both isomer series, the meta isomers being 10-fold more lipophilic than the analogous ortho porphyrins. Increasing the length of the alkyl chain by one carbon atom increases the log P(OW) value approximately 1 log unit with both isomers. Dramatic approximately 4 and approximately 5 orders of magnitude increases in the lipophilicity of the ortho isomers, by extending the pyridyl alkyl chains from two (MnTE-2-PyP, log P(OW)=-6.89) to six (MnTnHex-2-PyP, log P(OW)=-2.76) and eight carbon atoms (MnTnOct-2-PyP, log P(OW)=-1.24), parallels the increased efficacy in several oxidative-stress injury models, particularly those of the central nervous system, in which transport across the blood-brain barrier is critical. Although meta isomers are only slightly less potent SOD mimics and antioxidants than their ortho analogues, their higher lipophilicity and smaller bulkiness may lead to a higher cellular uptake and overall similar effectiveness in vivo.

Spectral, electrochemical, and catalytic properties of a homologous series of manganese porphyrins as cytochrome P450 model: The effect of the degree of β-bromination

A homologous series of beta-brominated porphyrins derived from meso-tetrakis(4-carbomethoxyphenyl)porphyrinatomanganese(III) chloride, i.e., Mn(III)(Br(x)TCMPP)Cl (x=0,2,4,6, and 8), was prepared and investigated as cytochrome P450 models. Hydroxylations of cyclohexane by iodosylbenzene (PhIO) and iodobenzene diacetate (PhI(OAc)(2)) in the presence or absence of water were carried out as P450 model reactions. The influence of the degree of beta-bromination of the macrocycle on the UV-vis spectra, the Mn(III)/Mn(II) reduction potential, and the catalytic properties of the Mn(III)(Br(x)TCMPP)Cl (x=0,2,4,6, and 8) series were examined. The catalytic efficiency does not correlate with the Mn(III)/Mn(II) reduction potential and shows a bell-shaped behavior, where the best results are achieved with the hexabrominated complex. Better hydroxylation yields were achieved by using PhI(OAc)(2) as oxygen donor, but at expenses of catalyst recovery; addition of water to this system resulted in a increase in the reaction rate. Recycling of the more oxidatively robust complexes Mn(III)(Br(6)TCMPP)Cl and Mn(III)(Br(8)TCMPP)Cl is feasible when using PhIO as oxygen donor. Selectivity and UV-vis data suggested that hydroxylation by both PhIO and PhI(OAc)(2) share closely related active species and mechanism. We also show that the Mn(III)/Mn(II) reduction potentials are inappropriate predictors of P450-type activity of Mn porphyrin-catalyzed oxidations.

New highly brominated Mn-porphyrin: a good catalyst for activation of inert C–H bonds

This work describes the synthesis and characterization of a novel third-generation catalyst 5,10,15,20-tetrakis-(4′-bromine-3′,5′-dimethoxyphenyl)-2,3,7,8,12,13,17,18-octabromoporphyrinatomanganese chloride [MnIIIBr12T3,5DMPP]Cl (Cat.2). The catalytic activity of Cat.2 in cyclohexane, adamantane, and n-hexane oxidation by iodosylbenzene (PhIO) or iodobenzene diacetate (PhI(OAc)2) was compared with the catalytic activity of [MnIIIT3,5DMPP]Cl (Cat.1), a second generation catalyst. The Cat.2/PhI(OAc)2 system led to higher yields of cyclohexane oxidation products (65%) with high selectivity for cyclohexanol (86%) as compared with Cat.1 (19% and 74%, respectively) and addition of water essentially did not alter total product yield. Addition of a small amount of imidazole to the Cat.1/PhIO system gave superior yields of cyclohexane oxidation products (64%) as compared with Cat.2 (52%). In all systems Cat.2 afforded significantly higher yields of 2-adamantanol, a product with great commercial value compared with 1-adamantanol. n-Hexane oxidation gave low total product yield; Cat.2 was more selective for alcohol products (2-hexanol and 3-hexanol).

Biomimetic oxidation of cyclic and linear alkanes: high alcohol selectivity promoted by a novel manganese porphyrin catalyst

A novel third-generation metalloporphyrin, chloro-5,10,15,20-tetrakis-(3′-bromine-4′-methoxyphenyl)-2,3,7,8,12,13,17,18-octabromoporphyrinatomanganese(III), [MnIIIBr12T4(-OMe)PPCl], designated as MnBr12Por, was synthesized and characterized. The catalytic activity of the new manganese porphyrin was investigated in the oxidation of cyclohexane, adamantane and n-hexane by iodosylbenzene (PhIO) or iodobenzene diacetate (PhI(OAc)2) in comparison to the catalytic activity of the second-generation catalyst [MnIIIT4(-OMe)PPCl], designated as MnPor. All yields were based on oxidants. The MnBr12Por/PhIO system led to higher yields of cyclohexane oxidation products (45%) with high selectivity for cyclohexanol (80%) as compared to the MnPor/PhIO system (23% and 77%, respectively). Addition of imidazole to MnPor/PhIO increased the total product yield from 23 to 43%; addition of imidazole to MnBr12Por/PhIO did not alter the total product yield at all. For the MnPor/PhI(OAc)2 and MnBr12Por/PhI(OAc)2 systems, addition of imidazole increased the product yields from 19 to 45% and from 35 to 66%, respectively. Addition of water increased the total product yields during cyclohexane and adamantane oxidation for all the studied systems. In all cases, MnBr12Por performed better than MnPor.