title: Degradation of camptothecin-20(S)-glycinate ester prodrug under physiological conditions.
abstract: We have compared the strikingly different decomposition pathways for camptothecin-20(S)-acetate -acetate and camptothecin-20(S)-glycinate in phosphate buffered saline, human plasma and blood. The aliphatic ester analog camptothecin-20(S)-acetate demonstrated excellent stability in the above fluids for many hours with minimal hydrolysis, while the camptothecin-20(S)-glycinate analog (differing solely by the presence of an amino group) underwent rapid and essentially complete decomposition. Reversed-phase high performance liquid chromatography (RP-HPLC) with electrospray ionization-mass spectral (ESI-MS) detection was then used to correlate structural information for camptothecin-20(S)-glycinate decomposition products. ESI-MS detection indicated the ring-opened carboxylate form of camptothecin and the ring-opened degradation product co-elute near the solvent front, while the latest eluting decomposition product was the closed-ring lactone form of camptothecin. A novel decomposition product with intermediate retention time displayed an identical mass-to-charge ratio as camptothecin-20(S)-glycinate ester but a strikingly different fragmentation pattern. The LC-ESI-MS evidence of a novel camptothecin prodrug degradation pathway is provided in this report.
authors.affiliation: Department of Chemistry, University of Kentucky, Room A053, ASTeCC Building, Lexington, KY 40506, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Liu
authors.forename: Junhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.forename: Bert C
authors.initials: BC
authors.lastname: Lynn
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Burke
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry*; D002853:Chromatography, Liquid; D004355:Drug Stability; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; C496829:camptothecin-20-glycinate ester; C097011:O-acetylcamptothecin; D005998:Glycine; D002166:Camptothecin