Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Dalton Trans. 2019 Aug 28;48(32):12040-12049. doi: 10.1039/c9dt02078k. Epub 2019 Jul 11.
Quadruplex nucleic acids - DNA/RNA secondary structures formed in guanine rich sequences - proved to have key roles in the biology of cancers and, as such, in recent years they emerged as promising targets for small molecules. Many reports demonstrated that metal complexes can effectively stabilize quadruplex structures, promoting telomerase inhibition, downregulation of the expression of cancer-related genes and ultimately cancer cell death. Although extensively explored as anticancer agents, studies on the ability of ruthenium arene complexes to interact with quadruplex nucleic acids are surprisingly almost unknown. Herein, we report on the synthesis and characterization of four novel Ru(ii) arene complexes with 1,3-dioxoindan-2-carboxamides ligands bearing pendant naphthyl-groups designed to bind quadruplexes by both stacking and coordinating interactions. We show how improvements on the hydrolytic stability of such complexes, by substituting the chlorido leaving ligand with pyridine, have a dramatic impact on their interaction with quadruplexes and on their cytotoxicity against ovarian cancer cells.
四链体核酸 - 在富含鸟嘌呤的序列中形成的 DNA/RNA 二级结构 - 已被证明在癌症的生物学中具有关键作用，因此近年来它们成为小分子的有前途的靶标。许多报告表明，金属配合物可以有效地稳定四链体结构，促进端粒酶抑制、下调与癌症相关的基因表达，最终导致癌细胞死亡。尽管作为抗癌剂进行了广泛的研究，但令人惊讶的是，关于钌芳烃配合物与四链体核酸相互作用的研究几乎是未知的。在此，我们报告了四种新型 Ru(ii)芳烃配合物的合成和表征，这些配合物带有 1,3-二氧代吲哚-2-甲酰胺配体，带有悬垂的萘基基团，旨在通过堆积和配位相互作用与四链体结合。我们展示了通过用吡啶取代氯配体来提高此类配合物的水解稳定性如何对它们与四链体的相互作用及其对卵巢癌细胞的细胞毒性产生重大影响。
