Division of Biological Inorganic Chemistry, State Key laboratory of Rare Earth Resources Utilization, Changchun Institute of Applied Chemistry, Graduate School of Chinese Academy of Sciences, Changchun, Jilin 130022, China.
Nucleic Acids Res. 2012 Sep;40(16):8186-96. doi: 10.1093/nar/gks524. Epub 2012 Jun 6.
There is great interest in design and synthesis of small molecules which selectively target specific genes to inhibit biological functions in which particular DNA structures participate. Among these studies, chiral recognition has been received much attention because more evidences have shown that conversions of the chirality and diverse conformations of DNA are involved in a series of important life events. Here, we report that a pair of chiral helical macrocyclic lanthanide (III) complexes, (M)-YbL(SSSSSS) and (P)-YbL(RRRRRR), can enantioselectively bind to B-form DNA and show remarkably contrasting effects on GC-rich and AT-rich DNA. Neither of them can influence non-B-form DNA, nor quadruplex DNA stability. Our results clearly show that P-enantiomer stabilizes both poly(dG-dC)(2) and poly(dA-dT)(2) while M-enantiomer stabilizes poly(dA-dT)(2), however, destabilizes poly(dG-dC)(2). To our knowledge, this is the best example of chiral metal compounds with such contrasting preference on GC- and AT-DNA. Ligand selectively stabilizing or destabilizing DNA can interfere with protein-DNA interactions and potentially affect many crucial biological processes, such as DNA replication, transcription and repair. As such, bearing these unique capabilities, the chiral compounds reported here may shed light on the design of novel enantiomers targeting specific DNA with both sequence and conformation preference.
人们对设计和合成能够选择性地靶向特定基因以抑制特定 DNA 结构参与的生物功能的小分子很感兴趣。在这些研究中，手性识别受到了广泛关注，因为越来越多的证据表明，DNA 的手性和构象转化参与了一系列重要的生命事件。在这里，我们报告一对手性螺旋大环镧系（III）配合物，（M）-Yb[L(SSSSSS)]（3+）和（P）-Yb[L(RRRRRR)]（3+），可以对 B 型 DNA 进行对映选择性结合，并对富含 GC 和富含 AT 的 DNA 表现出显著的对比效果。它们都不能影响非 B 型 DNA 或四链 DNA 的稳定性。我们的结果清楚地表明，P-对映异构体稳定了 poly(dG-dC)(2)和 poly(dA-dT)(2)，而 M-对映异构体稳定了 poly(dA-dT)(2)，但却破坏了 poly(dG-dC)(2)。据我们所知，这是手性金属化合物在手性对富含 GC 和富含 AT 的 DNA 具有如此对比偏好的最佳例子。配体选择性地稳定或破坏 DNA 可以干扰蛋白质-DNA 相互作用，并可能影响许多关键的生物过程，如 DNA 复制、转录和修复。因此，具有这些独特功能的手性化合物可能为设计具有序列和构象偏好的针对特定 DNA 的新型对映异构体提供思路。
