title: Reactions of {4-[bis(2-chloroethyl)amino]phenyl}acetic acid (phenylacetic acid mustard) with 2'-deoxyribonucleosides.
abstract: Phenylacetic acid mustard (PAM; 2), a major metabolite of the anticancer agent chlorambucil (CLB; 1), was allowed to react with 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), 2'-deoxycytidine (dC), 2'-deoxy-5-methylcytidine (dMeC), and thymidine (T) at physiological pH (cacodylic acid, 50% base). The reactions were followed by HPLC and analyzed by HPLC/MS and/or (1)H-NMR techniques. Although the predominant reaction observed was hydrolysis of PAM, 2 also reacted with various heteroatoms of the nucleosides to give a series of products: compounds 5-31. PAM (2) was found to be hydrolytically slightly more stable than CLB (1). The principal reaction sites of 2 with dA, dG, and with all pyrimidine nucleosides were N(1), N(7), and N(3), resp. Also, several other adducts were detected and characterized. There was no significant difference in the reactivity of 1 and 2 with dG, dA or T, but the N(3) dC-PAM adduct was deaminated easier than the corresponding CLB derivative. The role of PAM-2'-deoxyribonucleoside adducts on the cytotoxic and mutagenic properties of CLB (1) is discussed.
authors: Department of Chemistry, University of Turku, FIN-20014 Turku.
authors: Diana
authors: D
authors: Florea-Wang
authors: Inna
authors: I
authors: Ijäs
authors: Kristo
authors: K
authors: Hakala
authors: Jorma
authors: J
authors: Mattinen
authors: Juhani
authors: J
authors: Vilpo
authors: Jari
authors: J
authors: Hovinen
mesh_terms: D002699:Chlorambucil / Q000737:chemistry / Q000378:metabolism*; D003853:Deoxyribonucleosides / Q000737:chemistry / Q000378:metabolism*; D009150:Mustard Compounds / Q000737:chemistry / Q000378:metabolism*; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003853:Deoxyribonucleosides; D009150:Mustard Compounds; D010648:Phenylacetates; D002699:Chlorambucil; C025136:phenylacetic acid