Wang H, Gupta R, Lown J W
Department of Chemistry, University of Alberta, Edmonton, Canada.
Anticancer Drug Des. 1994 Jun;9(3):153-60.
The synthesis and characterization of two groups of N1-alkoxyalkyl-bis-benzimidazoles are described. These groups of agents, that differ in the orientation of the N3-alkoxyalkyl group with respect to the minor groove of the DNA receptor, were designed to examine the structural requirements of molecular recognition of these minor groove-selective anticancer agents. The relative binding of the 12 agents to poly(dA-dT), determined by ethidium displacement in C50 values, ranged from 0.62 to 14.20 micrograms/ml. Sequence-preferential binding, established by complementary strand MPE.Fe(II) footprinting, was predominantly AT selective, but with significantly enhanced GC recognition in the cases of those ligands bearing an accessible pyridine N directed inwards to the minor groove. Binding site sizes were generally 5 +/- 1 base pairs. Cytotoxicities against KB human tumor cells ranged from 0.93 to 46.59 micrograms/ml. The most potent agent 6c, which also showed the strongest DNA binding, is of the 'r-inward-directed' type. The stringent structural requirements within the alkoxyalkyl R group for potency suggest additional specific interactions or chemical reaction of 6c within the groove that more than compensate for the increased steric hindrance.
描述了两组N1-烷氧基烷基-双苯并咪唑的合成与表征。这两组试剂在N3-烷氧基烷基相对于DNA受体小沟的取向上有所不同，旨在研究这些小沟选择性抗癌剂分子识别的结构要求。通过在C50值下用溴化乙锭置换法测定的12种试剂与聚（dA-dT）的相对结合范围为0.62至14.20微克/毫升。通过互补链MPE.Fe（II）足迹法确定的序列优先结合主要是AT选择性的，但对于那些带有向内指向小沟的可及吡啶N的配体，GC识别显著增强。结合位点大小一般为5±1个碱基对。对KB人肿瘤细胞的细胞毒性范围为0.93至46.59微克/毫升。最有效的试剂6c，其也显示出最强的DNA结合，属于“r向内指向”类型。烷氧基烷基R基团内对效力的严格结构要求表明6c在沟内有额外的特定相互作用或化学反应，足以弥补增加的空间位阻。
