Application of chemical P-450 model systems to studies on drug metabolism. Part X. Novel hydroxylactonization of ?,?- and ?,?- unsaturated carboxylic acids with an iron porphyrin?iodosylbenzene system

The oxidative hydroxylactonization of gamma,delta- and beta,gamma-unsaturated carboxylic acids by a chemical cytochrome P-450 model and rat liver microsomal systems has been investigated. In the chemical system using meso-tetrakis(2,6-dichlorophenyl)porphyrin iron chloride [Fe(TDClPP)Cl] with iodosylbenzene (PhIO), gamma,delta-unsaturated carboxylic acids have been converted into delta-hydroxy-gamma-lactones in high yield and with high stereoselectivity, As an example of a beta,gamma-unsaturated carboxylic acid, indomethacin has been converted into the corresponding beta-hydroxy gamma-lactone. Several experiments directed toward mechanistic elucidation of the lactonization exclude a mechanism occurring via an epoxide intermediate, The products have been used as standards to identify the metabolites in the microsomal oxidation, In the case of indomethacin, the gamma-lactone form is detected as a metabolite in the rat liver microsomal system, in a yield of 1.33%; the yield is significantly decreased in the presence of 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF-525A) and under a mixed CO-O-2 (4:1) atmosphere. Thus, these metabolites are considered to be formed by a cytochrome P-450-dependent reaction.