The S-oxidative degradation of a novel corticosteroid tipredane (INN). Part II--Detailed investigations into the primary S-oxidation of tipredane using achiral oxidants.
The C-17 dithioketal moiety of the corticosteroid tipredane (INN,I) has been shown to undergo site and stereoselective S-oxidations with a range of achiral oxidants. S-Oxidation was favoured on the methylthio substitutent (beta-plane) in preference to the ethylthio substituent (alpha-plane) in a ratio of 1.8-3.5:1. S-Oxidation on both substituents appeared to be stereoselective yielding an approximate ratio of 4:1 and 1:3.5-6 for the S-:R-methyl and ethylsulphoxide diastereoisomers, (II and VI) respectively. The preferred sites for S-oxidation have been explained in terms of the preferred rotamers of the C-17 substituents and the steric factors imposed on the attack of the oxidant on the lone pair of electrons at each sulphur atom. Optimized HPLC conditions using a Hypersil ODS column and an acetonitrile-0.025 M NH4OAc pH 7.2 gradient at 26 degrees C were developed to prevent degradation of the ethylsulphoxide diastereoisomers (VI) occurring during chromatographic analysis, via elimination of ethylsulphenic acid to yield the corresponding C-17 vinylmethylthio derivative (VII).
Euerby
M R
MR
Analytical Chemistry Department, Fisons Pharmaceuticals PLC, Loughborough, Leicestershire, UK.
Johnson
C M
CM
Lewis
R J
RJ
Nichols
S C
SC
D000287:Administration, Topical; D000730:Androstadienes / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D005938:Glucocorticoids; D016877:Oxidants / Q000737:chemistry*; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000737:chemistry
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016877:Oxidants; D013454:Sulfoxides; C051756:tipredane