N,N-双（2-氯乙基）-对氨基苯基丁酸（苯丁酸氮芥）与2'-脱氧腺苷的反应

Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxyadenosine.

作者信息

Florea-Wang Diana, Haapala Elina, Mattinen Jorma, Hakala Kristo, Vilpo Juhani, Hovinen Jari

机构信息

Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.

出版信息

Chem Res Toxicol. 2003 Mar;16(3):403-8. doi: 10.1021/tx0256735.

DOI:10.1021/tx0256735

PMID:12641441

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.

摘要

N,N-双(2-氯乙基)-对氨基苯基丁酸（苯丁酸氮芥，1；0.6 mM）在生理pH值（二甲胂酸，50%碱）下与2'-脱氧腺苷（16.1 mM）反应，反应通过高效液相色谱-质谱联用（HPLC-MS）和高效液相色谱-串联质谱联用（HPLC-MS/MS）技术进行跟踪。尽管观察到的主要反应是苯丁酸氮芥水解，但约7%的1与核苷的各种杂原子发生了反应。烷基化的主要位点是N1。还检测到了其他几种加合物。通过串联质谱、紫外光谱和氢核磁共振（¹H NMR）对N1、N6、N3和N7衍生物进行了表征。N6加合物直接来源于2'-脱氧腺苷N6的烷基化。在所采用的反应条件下，N1加合物向N6加合物的迪姆罗思重排非常缓慢。通过串联质谱对诸如碳水化合物衍生物等次要加合物进行了初步表征。未检测到交联产物。还讨论了苯丁酸氮芥-2'-脱氧腺苷加合物在1的细胞毒性和致突变性中的作用。