Carbinolamines, imines, and oxazolidines from fluorinated propranolol analogs. (19)F NMR and mass spectral characterization and evidence for formation as intermediates in cytochrome P450-catalyzed N-dealkylation.
Formation of carbinolamine, imine, and oxazolidines from the reactions of desisopropylpropranolol (5), its O-methyl ether (10), and 3-(1-naphthoxy)propylamine (11) with trifluoroacetone and trifluoroacetaldehyde methyl hemiacetal was investigated by (19)F NMR and tandem mass spectrometry. Products from the metabolism of the related secondary amine substrates trifluoropropranolol (7), its O-methyl ether (23), and its N-trifluoroethyl-O-methyl ether analog (24) in the presence of rat liver microsomes and CYP1A2 were examined to determine whether these species were formed. The (19)F NMR experiments showed the presence of carbinolamine and imine species from these primary amines and fluorinated carbonyl compounds in solution. Mass spectral experiments under atmospheric pressure chemical ionization and electrospray ionization-ion trap conditions showed formation of imine metabolites (and/or oxazolidine from 7) as well as products of N-dealkylation and aromatic hydroxylation when the secondary amine substrates were incubated with rat liver microsomes or CYP1A2. In spite of mass spectral evidence for these imines as metabolites, we were unable to detect the carbinolamines under the conditions used in these studies. Their presence is inferred from the results of the (19)F NMR experiments.
Upthagrove
A L
AL
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Nelson
W L
WL
D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D007097:Imines / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009281:Naphthalenes / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism*; D011433:Propranolol / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
D007097:Imines; D009281:Naphthalenes; D010080:Oxazoles; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D019388:Cytochrome P-450 CYP1A2