STRUCTURAL CHARACTERIZATION OF 2 NOVEL OXIDATIVE DERIVATIVES OF CYCLOSPORINE GENERATED BY A CHEMICAL METHOD

Objectives: To study the generation of cyclosporine derivatives (CMs) by chemical oxidation of the parent compound using hydrogen peroxide. Methods and Results: Hydrogen peroxide was added to cyclosporine (CsA) , which was dissolved in ether. After liquid-liquid extraction, CMs we re purified by high performance liquid chromatography (HPLC). Detailed structures of CMs were determined by fast atomic bombardment mass spe ctrometry (FABMS) and nuclear magnetic resonance spectroscopy (NMR). O ur results indicated that the parent compound was modified at amino ac id number 1 by hydroxylation of the carbon and the formation of a tetr ahydrofuran five member ring structure. In addition, these two oxidati ve products of CsA were determined to be isomeric to each other, diffe ring only in the configuration at one or more carbon atoms. This modif ication is in contrast to that observed for the formation of the cycli c metabolite of CsA, namely AM1c, by cytochrome P-450 isoenzymes, wher e the addition of the hydroxyl group occurs on the carbon of amino aci d 1. Conclusion: 3 to 4 mg of 2 oxidative derivatives could be produce d from 5 mg of CsA by chemical modification of the parent compound. In comparison, biotransformation using the drug-induced hepatic microsom al enzyme system could only produce 0.5 to 1 mg of metabolites/derivat ives from 5 mg of CsA. Copyright (C) 1998 The Canadian Society of Clin ical Chemists.