Smaill J B, Fan J Y, Papa P V, O'Connor C J, Denny W A
Cancer Research Laboratory, School of Medicine, University of Auckland, New Zealand.
Anticancer Drug Des. 1998 Apr;13(3):221-42.
Two series of mono- and dysfunctional aniline mustards linked to a bisbenzimidazole minor groove binder have been prepared using a new method (polyphosphate ester-mediated direct coupling of appropriate mustard acids with a preformed advanced phenylenediamine intermediate). As the linker chain attaching the mustard was lengthened the binding site size of the compounds to calf thymus DNA remained essentially constant at 2.6 nucleotides, but reversible binding strength declined by a factor of 2. Analogues with longer linker chains alkylated DNA much more rapidly than those with shorter chains, consistent with the electronic factors. The short chain analogues also failed to alkylate a 120 bp HindIII to Bg/II fragment of the gpt gene, as measured by gel electrophoresis cleavage assays. The longer chain analogues (both mono- and dysfunctional mustards) showed patterns of DNA alkylation that varied with chain length. In particular, while most compounds showed substantial N7 alkylation at many guanine residues, the analogue with a (CH2)3 linker chain showed strong alkylation at adenine sites in poly-AT regions. For the longer chain analogues, the bifunctional mustards were substantially (10- to 20-fold) more cytotoxic than the corresponding monofunctional analogues.
利用一种新方法（多磷酸酯介导的适当芥子酸与预先形成的高级苯二胺中间体的直接偶联）制备了与双苯并咪唑小沟结合剂相连的两类单功能和功能失调的苯胺芥子气。随着连接芥子气的连接链变长，化合物与小牛胸腺DNA的结合位点大小基本保持在2.6个核苷酸不变，但可逆结合强度下降了2倍。连接链较长的类似物比连接链较短的类似物使DNA烷基化的速度快得多，这与电子因素一致。通过凝胶电泳切割分析测定，短链类似物也未能使gpt基因的120 bp HindIII至Bg/II片段烷基化。较长链的类似物（单功能和功能失调的芥子气）显示出DNA烷基化模式随链长而变化。特别是，虽然大多数化合物在许多鸟嘌呤残基处显示出大量的N7烷基化，但具有(CH2)3连接链的类似物在聚AT区域的腺嘌呤位点显示出强烈的烷基化。对于较长链的类似物，双功能芥子气的细胞毒性比相应的单功能类似物大得多（10至20倍）。
