Martin Jason N, Muñoz Eva M, Schwergold Caroline, Souard Florence, Asensio Juan Luis, Jiménez-Barbero Jesús, Cañada Javier, Vicent Cristina
Instituto de Química Orgánica, CSIC, c/ Juan de la Cierva 3, Madrid 28006, Spain.
J Am Chem Soc. 2005 Jul 6;127(26):9518-33. doi: 10.1021/ja050794n.
Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-DNA interactions. The general design of the ligands 1-3 has been done as to favor the bound conformation of Distamycin-type gamma-linked covalent dimers which is a hairpin conformation. Indeed, NMR analysis of the sugar-oligoamides in the free state has indicated the presence of a percentage of a hairpin conformation in aqueous solution. The DNA binding activity of compounds 1-3 was confirmed by calf thymus DNA (ct-DNA) NMR titration. Interestingly, the binding of the different sugar-oligoamides seems to be modulated by the sugar configuration. Semiquantitative structural information about the DNA ligand complexes has been derived from NMR data. A competition experiment with Netropsin suggested that the sugar-oligoamide 3 bind to DNA in the minor groove. The NMR titrations of 1-3 with poly(dA-dT) and poly(dG-dC) suggested preferential binding to the ATAT sequence. TR-NOE NMR experiments for the sugar-oligoamide 3-ct-DNA complex both in D(2)O and H(2)O have confirmed the complex formation and given information on the conformation of the ligand in the bound state. The data confirmed that the sugar-oligoamide ligand is a hairpin in the bound state. Even more relevant to our goal, structural information on the conformation around the N-glycosidic linkage has been accessed. Thus, the sugar asymmetric centers pointing to the NH-amide and N-methyl rims of the molecule have been characterized.
糖寡酰胺已被设计并合成,作为结构简单的基于碳水化合物的配体,用于研究碳水化合物与DNA的相互作用。配体1-3的总体设计旨在有利于Distamycin型γ-连接共价二聚体的结合构象,即发夹构象。实际上,对游离状态下的糖寡酰胺进行的NMR分析表明,在水溶液中存在一定比例的发夹构象。通过小牛胸腺DNA(ct-DNA)NMR滴定证实了化合物1-3的DNA结合活性。有趣的是,不同糖寡酰胺的结合似乎受糖构型的调节。关于DNA配体复合物的半定量结构信息已从NMR数据中获得。与纺锤菌素的竞争实验表明,糖寡酰胺3在小沟中与DNA结合。用聚(dA-dT)和聚(dG-dC)对1-3进行的NMR滴定表明,其优先与ATAT序列结合。对糖寡酰胺3与ct-DNA复合物在D₂O和H₂O中的TR-NOE NMR实验证实了复合物的形成,并给出了结合状态下配体构象的信息。数据证实,糖寡酰胺配体在结合状态下是发夹结构。与我们的目标更相关的是,已经获得了关于N-糖苷键周围构象的结构信息。因此,已经对指向分子的NH-酰胺和N-甲基边缘的糖不对称中心进行了表征。