A dinuclear ruthenium(ii) phototherapeutic that targets duplex and quadruplex DNA
A dinuclear ruthenium(ii) phototherapeutic that targets duplex and quadruplex DNA
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DOI：
10.1039/c8sc05084h
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发表时间：
2019-03-28
期刊：
影响因子：
8.4
通讯作者：
Thomas, James A.
中科院分区：
文献类型：
--
作者：
Archer, Stuart A.;Raza, Ahtasham;Thomas, James A.
为了开发用于光动力疗法的敏化剂，将先前报道的在活细胞中用作DNA探针的发光双核配合物修饰以产生含有Ru-II（TAP）（2）片段的新的同结构衍生物（TAP = 1，4，5，8-四氮杂菲）。新配合物的结构已通过包括单晶X射线分析在内的多种技术证实。与其母体不同，新的配合物在MeCN和水中均显示Ru L基（MLCT）-M-3发射。涉及鸟苷酸的电化学研究和发射猝灭实验的结果与位于TAP部分上的激发态一致。详细的DFT计算进一步支持了这一假设，该计算考虑了溶剂对激发态动力学的影响。无细胞的稳态和时间分辨光学研究的新的复合物与双链体和四链体DNA的相互作用表明，该复合物结合具有高亲和力的两种结构，并表明其光激发态也淬灭的DNA，一个过程是伴随着生成的鸟嘌呤自由基阳离子位点的光氧化产物。与母体复合物一样，这种新化合物被活细胞吸收，主要定位在细胞核内，在无光条件下显示出低细胞毒性。然而，与[{Ru-II（phen）（2）}（2）（tpphz）]（4+）完全相反，该新络合物被光治疗活化，对恶性人黑素瘤细胞系具有高度光毒性，这表明它是治疗这种恶性黑素瘤的有希望的先导物。
With the aim of developing a sensitizer for photodynamic therapy, a previously reported luminescent dinuclear complex that functions as a DNA probe in live cells was modified to produce a new iso-structural derivative containing Ru-II(TAP)(2) fragments (TAP = 1,4,5,8-tetraazaphenanthrene). The structure of the new complex has been confirmed by a variety of techniques including single crystal X-ray analysis. Unlike its parent, the new complex displays Ru L-based (MLCT)-M-3 emission in both MeCN and water. Results from electrochemical studies and emission quenching experiments involving guanosine monophosphate are consistent with an excited state located on a TAP moiety. This hypothesis is further supported by detailed DFT calculations, which take into account solvent effects on excited state dynamics. Cell-free steady-state and time-resolved optical studies on the interaction of the new complex with duplex and quadruplex DNA show that the complex binds with high affinity to both structures and indicate that its photoexcited state is also quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products. Like the parent complex, this new compound is taken up by live cells where it primarily localizes within the nucleus and displays low cytotoxicity in the absence of light. However, in complete contrast to [{Ru-II(phen)(2)}(2)(tpphz)](4+), the new complex is therapeutically activated by light to become highly phototoxic toward malignant human melanoma cell lines showing that it is a promising lead for the treatment of this recalcitrant cancer.