Intracellular targeting and pharmacological activity of the superoxide dismutase mimics MnTE-2-PyP5+ and MnTnHex-2-PyP5+ regulated by their porphyrin ring substituents

Inorg Chem. 2013 Apr 15;52(8):4121-3. doi: 10.1021/ic300700g. Epub 2013 Apr 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antioxidants / chemistry
  • Antioxidants / pharmacokinetics*
  • Antioxidants / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Metalloporphyrins / chemistry
  • Metalloporphyrins / pharmacokinetics*
  • Metalloporphyrins / pharmacology*
  • Superoxide Dismutase / chemistry*

Substances

  • Antioxidants
  • Metalloporphyrins
  • Mn(III) ortho-tetrakis(N-hexylpyridinium-2-yl)porphyrin
  • manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
  • Superoxide Dismutase