title: Intracellular targeting and pharmacological activity of the superoxide dismutase mimics MnTE-2-PyP5+ and MnTnHex-2-PyP5+ regulated by their porphyrin ring substituents.
abstract: Manganese porphyrin-based drugs are potent mimics of the enzyme superoxide dismutase. They exert remarkable efficacy in disease models and are entering clinical trials. Two lead compounds, MnTE-2-PyP(5+) and MnTnHex-2-PyP(5+), have similar catalytic rates, but differ in their alkyl chain substituents (ethyl vs n-hexyl). Herein we demonstrate that these changes in ring substitution impact upon drug intracellular distribution and pharmacological mechanism, with MnTnHex-2-PyP(5+) superior in augmenting menadione toxicity. These findings establish that both catalytic activity and intracellular distribution determine drug action.
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.forename: Emily L
authors.initials: EL
authors.lastname: Shearer
authors.forename: Niroshini M
authors.initials: NM
authors.lastname: Giles
authors.forename: Barry
authors.initials: B
authors.lastname: Lai
authors.forename: Stefan
authors.initials: S
authors.lastname: Vogt
authors.forename: Julio S
authors.initials: JS
authors.lastname: Reboucas
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Giles
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008665:Metalloporphyrins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D008665:Metalloporphyrins; C583825:Mn(III) ortho-tetrakis(N-hexylpyridinium-2-yl)porphyrin; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D013482:Superoxide Dismutase