Archer Stuart A, Raza Ahtasham, Dröge Fabian, Robertson Craig, Auty Alexander J, Chekulaev Dimitri, Weinstein Julia A, Keane Theo, Meijer Anthony J H M, Haycock John W, MacNeil Sheila, Thomas James A
Department of Chemistry , University of Sheffield , Brook Hill , Sheffield , S3 7HF , UK . Email:
Materials Science & Engineering , University of Sheffield , Mappin St , Sheffield S1 3JD , UK . Email:
Chem Sci. 2019 Feb 18;10(12):3502-3513. doi: 10.1039/c8sc05084h. eCollection 2019 Mar 28.
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(TAP) 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 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(phen)}(tpphz)], 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.
为了开发一种用于光动力疗法的敏化剂，对一种先前报道的在活细胞中用作DNA探针的发光双核配合物进行了修饰，以制备一种含有Ru(TAP)片段（TAP = 1,4,5,8-四氮杂菲）的新的同构衍生物。通过包括单晶X射线分析在内的多种技术确认了新配合物的结构。与母体不同，新配合物在MeCN和水中均显示基于Ru→L的MLCT发射。电化学研究结果以及涉及鸟苷单磷酸的发射猝灭实验结果与位于TAP部分的激发态一致。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。对新配合物与双链和四链DNA相互作用的无细胞稳态和时间分辨光学研究表明，该配合物与这两种结构都具有高亲和力结合，并表明其光激发态也被DNA猝灭，这一过程伴随着鸟嘌呤自由基阳离子位点作为光氧化产物的产生。与母体配合物一样，这种新化合物被活细胞摄取，主要定位于细胞核内，在无光条件下显示出低细胞毒性。然而，与[{Ru(phen)}(tpphz)]完全相反，新配合物经光激活后对恶性人类黑色素瘤细胞系具有高度光毒性，表明它是治疗这种难治性癌症的有前景的先导物。
