Structural characterization of two novel oxidative derivatives of cyclosporine generated by a chemical method.
OBJECTIVE
To study the generation of cyclosporine derivatives (CMs) by chemical oxidation of the parent compound using hydrogen peroxide.


RESULTS
Hydrogen peroxide was added to cyclosporine (CsA), which was dissolved in ether. After liquid-liquid extraction, CMs were purified by high performance liquid chromatography (HPLC). Detailed structures of CMs were determined by fast atomic bombardment mass spectrometry (FABMS) and nuclear magnetic resonance spectroscopy (NMR). Our results indicated that the parent compound was modified at amino acid number 1 by hydroxylation of the carbon and the formation of a tetrahydrofuran five member ring structure. In addition, these two oxidative products of CsA were determined to be isomeric to each other, differing only in the configuration at one or more carbon atoms. This modification is in contrast to that observed for the formation of the cyclic metabolite of CsA, namely AM1c, by cytochrome P-450 isoenzymes, where the addition of the hydroxyl group occurs on the carbon of amino acid 1.


CONCLUSIONS
3 to 4 mg of 2 oxidative derivatives could be produced from 5 mg of CsA by chemical modification of the parent compound. In comparison, biotransformation using the drug-induced hepatic microsomal enzyme system could only produce 0.5 to 1 mg of metabolites/derivatives from 5 mg of CsA.
Liu
W T
WT
Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.
Marat
K
K
Ren
Y
Y
Eng
R T
RT
Wong
P Y
PY
D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000737:chemistry* / Q000302:isolation & purification; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D016339:Spectrometry, Mass, Fast Atom Bombardment
D016572:Cyclosporine