title: New PEG-ylated Mn(III) porphyrins approaching catalytic activity of SOD enzyme.
abstract: Two new tri(ethyleneglycol)-derivatized Mn(III) porphyrins were synthesized with the aim of increasing their bioavailability, and blood-circulating half-life. These are Mn(III) tetrakis(N-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)pyridinium-2-yl)porphyrin, MnTTEG-2-PyP5+ and Mn(III) tetrakis(N,N'-di(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)imidazolium-2-yl)porphyrin, MnTDTEG-2-ImP5+. Both porphyrins have ortho pyridyl or di-ortho imidazolyl electron-withdrawing substituents at meso positions of the porphyrin ring that assure highly positive metal centered redox potentials, E1/2 = +250 mV vs. NHE for MnTTEG-2-PyP5+ and E1/2 = + 412 mV vs. NHE for MnTDTEG-2-ImP5+. As expected, from established E1/2 vs. log kcat(O2 *-) structure-activity relationships for metalloporphyrins (Batinic-Haberle et al., Inorg. Chem., 1999, 38, 4011), both compounds exhibit higher SOD-like activity than any meso-substituted Mn(III) porphyrins-based SOD mimic thus far, log kcat = 8.11 (MnTTEG-2-PyP5+) and log kcat = 8.55 (MnTDTEG-2-ImP5+), the former being only a few-fold less potent in disproportionating O2*- than the SOD enzyme itself. The new porphyrins are stable to both acid and EDTA, and non toxic to E. coli. Despite elongated substituents, which could potentially lower their ability to cross the cell wall, MnTTEG-2-PyP5+ and MnTDTEG-2-ImP5+ exhibit similar protection of SOD-deficient E. coli as their much smaller ethyl analogues MnTE-2-PyP5+ and MnTDE-2-ImP5+, respectively. Consequently, with anticipated increased blood-circulating half-life, these new Mn(III) porphyrins may be more effective in ameliorating oxidative stress injuries than ethyl analogues that have been already successfully explored in vivo.
authors.affiliation: Department of Radiation Oncology, Duke University Medical School, Durham, NC 27710, USA. ibatinic@duke.edu
authors.forename: Ines
authors.initials: I
authors.lastname: Batinić-Haberle
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojević
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Bruce
authors.initials: B
authors.lastname: Bondurant
authors.forename: Ayako
authors.initials: A
authors.lastname: Okado-Matsumoto
authors.forename: Irwin
authors.initials: I
authors.lastname: Fridovich
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujasković
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D004926:Escherichia coli / Q000201:enzymology; D008345:Manganese / Q000737:chemistry*; D011092:Polyethylene Glycols; D011166:Porphyrins / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013482:Superoxide Dismutase / Q000502:physiology*
chemical_list: D011166:Porphyrins; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D008345:Manganese; D013482:Superoxide Dismutase