Functionalized metalloporphyrin catalysts as cytochrome P450 enzyme mimics

• Online Access: http://hdl.handle.net/2047/D20211237

The structural and mechanistic similarities between metalloporphyrin (MP) catalysts and the heme-cofactor of cytochrome P450 (CYP) oxygenase enzymes (heme B), have made MPs one of the most viable options for biomimetic catalysis. In heme-monooxygenase enzymes, the amino acid ligate contributes substantially to enzyme function; as CYP and peroxidase enzymes are protein-bound by cysteine(SH) and histidine(ImN), respectively, (N)-containing heterocyclic mercaptans were an idyllic class of compounds to investigate as novel axial ligates. The in situ affinity of these ligates for the iron catalysts was extrapolated from charge transfer (CT) transitions of electronic spectra. The effect of the novel axial ligands, as well as other (S)- and/or (N)-containing axial ligands that vary in pK_a (2.8 - 11.2), size, and heteroatomic identity, was assessed using acetaminophen prodrugs as test substrates. Prodrug design that targets CYP enzymes has gained interest of recent, and targeting prodrugs using MPs offers an even greater range of applicability. The thiolate ligands afforded the greatest yields of acetaminophen in the majority of cases. Furthermore, (S)- and (N)-containing ligands were observed to promote different reaction pathways, regardless of pK_a or ligand size. The MP-mediated oxidation of current FDA-approved pharmaceuticals was then performed utilizing a functionalized iron (III) MP catalyst (octabromo or octachloro- substituted at the β-pyrrole positions), under both conventional and microwave conditions. Methods were developed to screen for the oxidative metabolites using selected-ion monitoring (SIM) and selected-reaction monitoring (SRM) mode MS/MS analyses.