Intracellular Targeting and Pharmacological Activity of the Superoxide Dismutase Mimics MnTE-2-PyP5+ and MnTnHex-2-PyP5+ Regulated by Their Porphyrin Ring Substituents

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• 作者：Jade B. Aitken ; Emily L. Shearer ; Niroshini M. Giles ; Barry Lai ; Stefan Vogt ; Julio S. Reboucas ; Ines Batinic-Haberle ; Peter A. Lay ; Gregory I. Giles
• 刊名：Inorganic Chemistry
• 出版年：2013
• 出版时间：April 15, 2013
• 年：2013
• 卷：52
• 期：8
• 页码：4121-4123
• 全文大小：199K
• 年卷期：v.52,no.8(April 15, 2013)
• ISSN：1520-510X

文摘

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-PyP⁵⁺ and MnTnHex-2-PyP⁵⁺, 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-PyP⁵⁺ superior in augmenting menadione toxicity. These findings establish that both catalytic activity and intracellular distribution determine drug action.