title: The carcinogenic significance of reactive intermediates derived from 3-acetoxy- and 5-acetoxy-2-hydroxy-N-nitrosomorpholine.
abstract: N-Nitroso-2-hydroxymorpholine (NHMOR), a relatively reactive metabolite of two potent carcinogens, N-nitrosodiethanolamine (NDELA) and N-nitrosomorpholine (NMOR), has been reported to not be carcinogenic. Two isomeric acetate esters of the alpha-hydroxynitrosamines expected to be produced from the cytochrome P450-mediated metabolism of NHMOR have been synthesized, and their hydrolytic decomposition products, hydrolysis rates, and deoxyguanosine (dG) reaction adducts have been determined. N-Nitroso-3-acetoxy-2-hydroxymorpholine was prepared in high yield from the reaction of N-nitroso-2,3-dehydromorpholine with dry peracetic acid in glacial acetic acid or by the reaction of its dimethyldioxirane-produced epoxide with glacial acetic acid. The hydrolysis of this alpha-acetoxynitrosamine gave acetaldehyde (10%), ethylene glycol (55%), glyoxal (95%), and acetic acid. The pH rate profile for the hydrolysis of this nitrosamine was abnormal in that it exhibited pronounced base-catalyzed hydrolysis beginning at pH 5. The mechanism of hydrolytic decomposition is proposed to involve neighboring group participation with the formation of a reactive epoxide intermediate. N-Nitroso-3-acetoxy-2-hydroxymorpholine reacted with dG to give these guanine adducts after acidic deglycosylation: 1,N2-glyoxal (65%), 7-(2-hydroxyethyl)guanine (9%), and O6-hydroxyethylguanine (3%). N-Nitroso-5-acetoxy-2-hydroxymorpholine was synthesized from 2-hydroxyethylvinylnitrosamine by its oxidative conversion to the corresponding aldehyde followed by reaction with dry peracetic acid in glacial acetic. The hydrolytic decomposition products of this nitrosamine were 2-acetoxyacetaldehyde (65%), a rearrangement product, glycol aldehyde (15%), a trace of glyoxal, and acetic acid. The pH rate profile for the hydrolysis of this acetate is similar to other alpha-acetoxynitrosamines in that it exhibits a pH-independent region which gives way to base-catalyzed ester hydrolysis beginning at pH 7. The lower pH ( approximately 7 < 9) onset of base catalysis is proposed to involve base-catalyzed opening of the hemiacetal and intramolecular acyl transfer to give an unstable alpha-hydroxynitrosamine. N-Nitroso-5-acetoxy-2-hydroxymorpholine was less reactive toward dG and gave the 1,N2-etheno-dG adduct (44%). The products from both of the isomeric alpha-acetoxy nitrosamines were judged to arise from diazonium ions produced from unstable alpha-hydroxynitrosamine intermediates. The high yield of the rearrangement product 2-acetoxyacetaldehyde could explain the low carcinogenic potential of NHMOR if it is mainly alpha-hydroxylated at the 5 carbon. Hydroxylation of NHMOR at carbon 3 is expected to yield a carcinogenic outcome.
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA. LoeppkyR@missouri.edu
authors.forename: Richard N
authors.initials: RN
authors.lastname: Loeppky
authors.forename: Sunil
authors.initials: S
authors.lastname: Sukhtankar
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Misun
authors.initials: M
authors.lastname: Park
mesh_terms: D000085:Acetates / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D006868:Hydrolysis; D007536:Isomerism; D007700:Kinetics; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry*; D009602:Nitrosamines / Q000737:chemistry*; D009603:Nitroso Compounds / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000737:chemistry*
chemical_list: C509526:3-acetoxy-2-hydroxy-N-nitrosomorpholine; C509527:5-acetoxy-2-hydroxy-N-nitrosomorpholine; D000085:Acetates; D002273:Carcinogens; D009025:Morpholines; D009602:Nitrosamines; D009603:Nitroso Compounds; D017382:Reactive Oxygen Species; C002741:N-nitrosomorpholine