title: Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxyadenosine.
abstract: N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 0.6 mM) was allowed to react with 2'-deoxyadenosine (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were followed by HPLC-MS and HPLC-MS/MS techniques. Although the predominant reaction observed was chlorambucil hydrolysis, ca. 7% of 1 reacted with various heteroatoms of the nucleoside. The principal site of alkylation was N1. Several other adducts were also detected. The N1, N6, N3, and N7 derivatives were characterized by means of MS/MS, UV, and (1)H NMR. The N6 adduct is derived directly from alkylation of N6 of 2'-dAdo. Dimroth rearrangement of the N1 adduct to the N6 adduct was very slow under the reaction conditions employed. Minor adducts such as a carbohydrate derivative were tentatively characterized by MS/MS. No cross-links were detected. The role of chlorambucil-2'-deoxyadenosine adducts in the cytotoxicity and mutagenicity of 1 is also discussed.
authors.affiliation: Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
authors.forename: Diana
authors.initials: D
authors.lastname: Florea-Wang
authors.forename: Elina
authors.initials: E
authors.lastname: Haapala
authors.forename: Jorma
authors.initials: J
authors.lastname: Mattinen
authors.forename: Kristo
authors.initials: K
authors.lastname: Hakala
authors.forename: Juhani
authors.initials: J
authors.lastname: Vilpo
authors.forename: Jari
authors.initials: J
authors.lastname: Hovinen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D002699:Chlorambucil / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry; D003839:Deoxyadenosines / Q000737:chemistry*; D006868:Hydrolysis; D013057:Spectrum Analysis / Q000379:methods
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D003839:Deoxyadenosines; D002699:Chlorambucil; C058118:2'-deoxyadenosine