School of Chemistry, Trinity Biomedical Sciences Institute, University of Dublin, Trinity College, Pearse St., Dublin 2, Ireland.
J Med Chem. 2012 May 10;55(9):4397-406. doi: 10.1021/jm300296f. Epub 2012 Apr 26.
In this paper we report the design and synthesis of a new family of asymmetric peptide linked diaromatic dications as potent DNA minor groove binders. These peptide-linked compounds, with a linear core, displayed a much larger affinity than other guanidinium-like derivatives from the same series with curved cores. As a first screening, the DNA affinity of these structures was evaluated by means of thermal denaturation experiments, finding that the nature of the cation (guanidinium vs 2-aminoimidazolinium) significantly influenced the binding strength. Their binding affinity was assessed by implementing further biophysical measurements such as surface plasmon resonance and circular dichroism. In particular, it was observed that compounds 6, 7, and 8 displayed both a strong binding affinity and significant selectivity for AT oligonucleotides. In addition, the thermodynamics of their binding was evaluated using isothermal titration calorimetry, indicating that the binding is derived from favorable enthalpic and entropic contributions.
本文报道了一类新型不对称肽连接的双芳基二阳离子的设计与合成，它们是具有潜力的 DNA 小沟结合物。这些具有线性核心的肽连接化合物比同一系列中具有弯曲核心的其他胍类似物具有更大的亲和力。作为初步筛选，通过热变性实验评估了这些结构的 DNA 亲和力，发现阳离子的性质（胍基与 2-氨基咪唑啉基）显著影响结合强度。通过实施进一步的生物物理测量，如表面等离子体共振和圆二色性，评估了它们的结合亲和力。特别是，观察到化合物 6、7 和 8 对 AT 寡核苷酸表现出强的结合亲和力和显著的选择性。此外，使用等温滴定量热法评估了它们结合的热力学，表明结合源于有利的焓和熵贡献。
