α-二氨基丁酸连接的发夹型聚酰胺
Alpha-diaminobutyric acid-linked hairpin polyamides.
作者信息
Farkas Michelle E, Tsai Sherry M, Dervan Peter B
机构信息
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
出版信息
Bioorg Med Chem. 2007 Nov 15;15(22):6927-36. doi: 10.1016/j.bmc.2007.07.019. Epub 2007 Aug 22.
A hairpin polyamide-chlorambucil conjugate linked by alpha-diaminobutyric acid (alpha-DABA) has been shown to have interesting biological properties in cellular and small animal models. Remarkably, this new class of hairpin polyamides has not been previously characterized with regard to energetics and sequence specificity. Herein we present a series of pyrrole-imidazole hairpin polyamides linked by alpha-DABA and compare them to polyamides containing the standard gamma-DABA turn unit. The alpha-DABA hairpins have overall decreased binding affinities. However, alpha-DABA polyamide-chlorambucil conjugates are sequence-specific DNA alkylators with increased specificities. Affinity cleavage studies of alpha-DABA polyamide-EDTA conjugates confirmed their preference for binding DNA in a forward hairpin conformation. In contrast, an unsubstituted glycine-linked polyamide prefers to bind in an extended binding mode. Thus, substitution on the turn unit locks the alpha-DABA polyamide into the forward hairpin binding motif.
一种通过α-二氨基丁酸（α-DABA）连接的发夹状聚酰胺-苯丁酸氮芥缀合物已在细胞和小动物模型中显示出有趣的生物学特性。值得注意的是，这类新型发夹状聚酰胺以前尚未在能量学和序列特异性方面进行过表征。在此，我们展示了一系列通过α-DABA连接的吡咯-咪唑发夹状聚酰胺，并将它们与含有标准γ-DABA转角单元的聚酰胺进行比较。α-DABA发夹的整体结合亲和力有所降低。然而，α-DABA聚酰胺-苯丁酸氮芥缀合物是序列特异性DNA烷基化剂，特异性有所增加。对α-DABA聚酰胺-EDTA缀合物的亲和切割研究证实了它们倾向于以前向发夹构象结合DNA。相比之下，未取代的甘氨酸连接的聚酰胺更倾向于以延伸的结合模式结合。因此，转角单元上的取代将α-DABA聚酰胺锁定在前向发夹结合基序中。
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