Microbial Oxidation of KE-298 Metabolites by Rhizopus sp. and Rhodococcus sp. Strains

概要

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The metabolites of the antirheumatic agent KE-298 in humans, (-)-(2R)-M-4 [(-)-(2R)-4-(4-hydroxymethylphenyl)-2-methylthiomethyl-4-oxobutanoic acid], (-)-(2R)-M-5 [diastereomers of (-)-(2R)-4-(4-hydroxymethylphenyl)-2-methylsulfinyl-methyl-4-oxobutanoic acid], (-)-(2R)-M-6 [(-)-(2R)-4-(4-carboxyphenyl)-2-methylthiomethyl-4-oxobutanoic acid], and (-)-(2R)-M-7 [diastereomers of (-)-(2R)-4-(4-carboxyphenyl)-2-methylsulfinylmethyl-4-oxobutanoic acid] were synthesized based on microbial transformation. The substrate KE-748 (racemic form of (-)-(2R)- and (+)-(2S)-4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid : 7.5g) was converted to (-)-(2R)-M-4 (1.84g) using Rhizopus sp. TF0040 in a 50-1 jar fermentor. Specific cytochrome P-450 inhibitors, SKF-525-A and metyrapone strongly inhibited the hydroxylation reaction. It was suggested that cytochrome P-450 is responsible for the microbial reaction. Furthermore, (-)-(2R)-M-4 (200 mg) was transformed to (-)-(2R)-M-6 (144 mg) by co-oxidation with n-hexadecane as a carbon source using Rhodococcus sp. TA0250 in a 1.4ljar fermentor. Starting from (-)-(2R)-M-4 and (-)-(2R)-M-6 obtained as above, (-)-(2R)-M-5 and (-)-(2R)-M-7,respectively were chemically synthesized by m-chloroperoxybenzoic acid oxidation.
社団法人日本農芸化学会の論文
1998-06-23