Biomimetic models for monooxygenases

Abstract

The microsomal mixed function oxidase system contains the cytochrome P-450 oxidative drug metabolizing family of enzymes, The catalytic cycle of cytochrome P-450 is believed to involve the formation of an active iron-oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co-reactants in most oxidative reactions of microsomal cytochrome P-450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P-450 in hydroxylation, exposidation, sulfoxidation, and N-demethylation of various drugs. The existance of an iron-oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p-450.Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed.The present paper reviews the various biomimetic models of the heme cytochrome P-450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and industrial applications.KEY WORDS Biomimetic models Cytochrome P-450 Drug metabolism

Photophysical, Electrochemical, and Theoretical Study of Protriptyline in Several Solvents

“…Under direct excitation of DBCH, radicals may be produced from its triplet state under oxidative conditions. 24,25 According to our data, oxygen quenches the PTL-HCl triplet state with a bimolecular rate constant in the range of (4.37-7.54) × 10 8 M -1 s -1 . Obviously, this explains why there is no dimer formation.…”

In vitro metabolism of 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one, a topical antipsoriatic agent. Use of precision-cut rat, dog, monkey and human liver slices, and chemical synthesis of metabolites

“…Complexation of this electron-rich pyridone oxygen atom to a high-valent, electrondeficient iron-oxo species within hepatic cytochrome P-450 would facilitate hydrogen loss from C (6). Hydrogen atom abstraction would occur through a six membered, cyclic transition state [25,26]. Finally, the loss of a C(6) hydrogen would create a resonance-stabilized radical conjugated through the central double bond (D 5a,9a ) to the lonepair electrons of the pyridone nitrogen atom.…”

The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application

“…159 The oxidative pathway of stilbene and its tricyclic derivatives with both Fenton (Fe(II)/H 2 O 2 ) and Ruff (Fe(III)/H 2 O 2 ) reagents was reported as a biomimetic simulation for the oxidative metabolism of cytochrome P-450 activation, which plays a significant role in chemical carcinogenesis. 160 The reaction of 5-dibenzosuberenone (1) with Fenton reagent resulted in the formation of trans-10,11-dihydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (249), α-hydroxy ketone 250, triketone 40, and aldehyde derivative 251 in addition to the major product epoxide 50 in 52% yield (Scheme 39). The results obtained suggested that the risk of mutagenicity of 1 will probably be reduced due to the relatively high stability of the oxirane ring in 50.…”