Specificity in the enzymic conversion of substituted cis-8, cis-11, cis-14-eicosatrienoic acids into prostaglandins

The enzyme specificity in the biosynthesis of prostaglandins has been investigated by incubation of a particulate fraction of sheep vesicular glands with substituted cis-8,cis-11,cis-14-eicosatrienoic acids. Conversions were always lower than with the unsubstituted acid (20:3). In the 2-substituted series, a conversion of up to 50% was found for 2-methoxycarbonyl- ; 2-methyl- ; 2-hydroxymethyl- ; 2-butyl- ; 2-methoxy- ; 2-methoxymethylene- ; 2-fluoro- ; 2-bromo- ; 2-cyano- ; and 2-phenyl-20:3. No conversion was found for 2-hydroxycarbonyl- ; 2-heptoxycarbonyl- ; 2-amino- ; and 2-acetamido-20:3. In some cases, a slight preference of the enzymes for the R configuration (2-phenyl- ; 2-methyl-20:3) was noted. For di-substituted acids, yields of up to 70% were found for 2-cyano-2-butyl- ; 2,3-cis- and 2,3-trans-methylene- ; 3,3-dimethyl-20:3, but 4,4-dimethyl-20:3 was not converted. However, 5-yne-20:3 was again a substrate (25% conversion). Substitution at the methyl end of the precursor acid resulted in 34% conversion with 19-methyl-20:3, but 18-methyl-20:3 was not converted. Biological activities of substituted prostaglandins were, in general, much less than those of PGE1, but for 19-methyl-PGE1, smooth muscle-stimulating activity was 1.6 times that of PGE1. For some substituted prostaglandins (2-fluoro- ; 2-cyano-PGE1), an appreciable activity in one biological test system was found but very little in others.