engleski

Increased Lipophilicity of meta Mn(III)N-alkylpiridylporphyrins, when Compared to ortho isomers, Fully Compensates for their Lower SOD-like Activity when Protecting SOD-defcient E.coli

Our growing insight into the in vivo action of SOD mimics have revealed that both antioxidant capacity (as a result of thermodynamics and electrostatics of the metal site) and bioavailability of a compound determine its in vivo efficacy. Thus, ill-designed compounds that lack either of these properties will be of compromised efficacy in vivo. Bioavailibility is greatly influenced by the lipophilicity, size, charges, bulkiness and substituents on porphyrins. We showed recently that a ~10-fold gain in lipophilicity is achieved by either (1) moving the alkyl groups from ortho to meta positions of meso pyridyl substituents, or (2) by increasing the length of alkyl chains by one CH2 group. Although the first evidence on the significant in vivo efficacy of meta Mn(III) N-methylpyridylporphyrin (MnTE-3-PyP5+) was published in J Biol Chem 1998, meta isomers have remained overlooked for over a decade, as most of the research has been direct towards designing catalytically potent SOD mimics. We show here that whereas meta isomers are 3.6- to 15-fold less potent SOD mimics, they are 10-fold more lipophilic and accumulate more in E. coli than their ortho analogues ; this altogether renders them highly able to protect SOD-deficient E.coli. In the most obvious case with alkyl being ethyl, meta isomer MnTE-3-PyP5+ is 10-fold less potent SOD mimic but is 10-fold more lipophilic than the ortho analogue MnTE-2-PyP5+(AEOL10113). Due to the higher lipophilicity and greater planarity plus conformational flexibility, the meta isomer crosses membranes easier, which leads to a 10-fold higher cytosolic accumulation than the standard SOD mimic MnTE-2-PyP5+. Higher accumulation in a cytosol overcomes its inferior thermodynamics for O2.- dismutation ; in turn both isomers exert identical ability to compensate for the lack of cytosolic SOD inSOD-deficient E. coli. The meta isomers of the N-pyridylporphyrins present, therefore, new opportunities for the design and development of SOD mimics of tailored activity and bioavailability. Support: National Institutes of Health grants[U19AI067798] and [5-P30-CA14236-29], W.H. Coulter Translational Partners Grant Program, Kuwait University grantMB03/07, and Universidade Federal da Paraíba and The Brazilian National Research Council (CNPq).

Mn(III)porfirini; lipofilnost; E. coli

nije evidentirano