Orally available Mn porphyrins with superoxide dismutase and catalase activities.
Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins, have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds are potential oral therapeutic agents for cellular damage caused by oxidative stress.
Rosenthal
Rosalind A
RA
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
Huffman
Karl D
KD
Fisette
Leslie W
LW
Damphousse
Christy A
CA
Callaway
Wyeth B
WB
Malfroy
Bernard
B
Doctrow
Susan R
SR
D000284:Administration, Oral; D000818:Animals; D055162:Biocatalysis; D001682:Biological Availability; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D008345:Manganese / Q000378:metabolism*; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism*
D008665:Metalloporphyrins; D008345:Manganese; D002374:Catalase; D013482:Superoxide Dismutase; D019311:Staurosporine