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Reactions of 4‐[Bis(2‐chloroethyl)amino]benzenebutanoic Acid (Chlorambucil) with DNA
Author(s) -
FloreaWang Diana,
Pawlowicz Agnieszka J.,
Sinkkonen Jari,
Kronberg Leif,
Vilpo Juhani,
Hovinen Jari
Publication year - 2009
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200800327
Subject(s) - chlorambucil , adduct , chemistry , dna , hydrolysate , stereochemistry , dna adduct , biochemistry , organic chemistry , biology , genetics , chemotherapy , hydrolysis , cyclophosphamide
4‐[Bis(2‐chloroethyl)amino]benzenebutanoic acid (=chlorambucil, 1 ; 2.5 m M ) was allowed to react with single‐ and double‐stranded calf thymus DNA at physiological pH (cacodylic acid, 50% base) at 37°. The DNA–chlorambucil adducts were identified by analyzing the DNA hydrolysates by NMR, UV, HPLC, LC/ESI‐MS/MS techniques as well as by spiking with authentic materials. ssDNA was more reactive than dsDNA, and the order of reactivity in ssDNA was Ade‐N1>Gua‐N7>Cyt‐N3>Ade‐N3. The most reactive site in dsDNA was Ade‐N3. The Gua‐N7 and Ade‐N3 adducts were hydrolytically labile. Ade‐N7 adduct could not be identified in the hydrolysates of ssDNA or dsDNA. The adduct Gua‐N7,N7, which consists of two units of Gua bound together with a unit derived from chlorambucil, is a cross‐linking adduct, and it was detected in the hydrolysates of ssDNA and dsDNA. Also several other adducts were detected which could be characterized by spiking with previously isolated authentic adducts or tentatively by MS. The role of chlorambucil–DNA adducts on the cytotoxicity and mutagenity of 1 is also discussed.

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