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Chem Biol. 1997 Nov;4(11):845-58.

Amphiphilic peroxynitrite decomposition catalysts in liposomal assemblies.

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  • 1Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.



Peroxynitrite (ONOO-), a toxic biological oxidant, has been implicated in many pathophysiological conditions. The water-soluble porphyrins 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron(III) (FeTMPyP) and manganese(III) (MnTMPyP) have recently emerged as potential drugs for ONOO- detoxification, and FeTMPyP has demonstrated activity in models of ONOO- related disease states. We set out to develop amphiphilic analogs of FeTMPyP and MnTMPyP suitable for liposomal delivery in sterically stabilized liposomes (SLs).


Three amphiphilic iron porphyrins (termed 1a-c.) and three manganese porphyrins (termed 2a-c.) bound to liposomes and catalyzed the decomposition of ONOO-. The polyethylene-glycol-linked metalloporphyrins 1b. and 2b. proved the most effective of these catalysts, rapidly decomposing ONOO- with second-order rate constants (kcat) of 2.9 x 10(5) M-1 s-1 and 5.0 x 10(5) M-1 s-1, respectively, in dimyristoylphosphatidylcholine liposomes. Catalysts 1b. and 2b. also bound to SLs, and these metalloporphyrin-SL constructs efficiently catalyzed ONOO- decomposition (kcat approximately 2 x 10(5) M-1 s-1). The analogous metalloporphyrins 1a. and 2a., which are not separated from the vesicle membrane surface by polyethylene glycol linkers, were significantly less effective (kcat approximately 3.5 x 10(4) M-1 s-1).


For these amphiphilic analogs of FeTMPyP and MnTMPyP, the polarity of the environment of the metalloporphyrin headgroup is intimately related to the efficiency of the catalyst; a polar aqueous environment is essential for effective catalysis of ONOO- decomposition. Thus, catalysts 1b. and 2b. react rapidly with ONOO- and are potential therapeutic agents that, unlike their water-soluble TMPyP analogs, could be administered as liposomal formulations in SLs. These SL-bound amphiphilic metalloporphyrins may prove to be highly effective in the exploration and treatment of ONOO- related disease states.

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