Intracellular
Targeting and Pharmacological Activity of the Superoxide Dismutase
Mimics MnTE-2-PyP<sup>5+</sup> and MnTnHex-2-PyP<sup>5+</sup> Regulated
by Their Porphyrin Ring Substituents
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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<sup>5+</sup> and MnTnHex-2-PyP<sup>5+</sup>, have similar catalytic rates, but differ in their alkyl
chain substituents (ethyl vs <i>n</i>-hexyl). Herein we
demonstrate that these changes in ring substitution impact upon drug
intracellular distribution and pharmacological mechanism, with MnTnHex-2-PyP<sup>5+</sup> superior in augmenting menadione toxicity. These findings
establish that both catalytic activity and intracellular distribution
determine drug action