Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; National Centre for Mass Spectrometry in Beijing; Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.
College of Chemistry and Materials Science, Key Laboratory of Functional Molecular Solids, the Ministry of Education, Anhui Laboratory of Molecular-Based Materials, Anhui Normal University, Wuhu 241000, P. R. China.
Dalton Trans. 2023 Sep 13;52(35):12478-12489. doi: 10.1039/d3dt01661g.
Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)Ru(L)] (1-4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)(phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (O), and their anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced O generation and complex 4 by binding to DNA.
钌（II）多吡啶配合物由于其光物理性质和抗癌活性而受到越来越多的关注。本文报道了四种钌（II）多吡啶配合物[（N^N）Ru（L）]（1-4，L = 4-苯胺基喹唑啉衍生物，N^N = 双齿配体，具有双氮供体）作为多功能抗癌剂。表皮生长因子受体（EGFR）在广泛的癌细胞中过度表达，与多种恶性肿瘤有关。表皮生长因子抑制剂，如吉非替尼和厄洛替尼，已被批准为临床抗癌药物。EGFR 抑制的 4-苯胺基喹唑啉配体大大增强了这些与一系列人癌细胞系相比，[Ru（bpy）（phen）]的抗癌活性，但有趣的是，这些配合物实际上不是有效的 EGFR 抑制剂。进一步的机制研究表明，在可见光照射下，配合物 3 和 4 产生了高水平的单线态氧（O），它们对人非小细胞肺癌（A549）、宫颈癌（HeLa）和鳞状细胞癌（A431）的抗癌活性得到了显著提高。具体来说，配合物 3 在蓝光照射下表现出很强的光毒性，其对 HeLa 和 A431 细胞的光毒性指数（PI）分别为 11 和 8.3。这些配合物在约 450nm 激发时在 600nm 处表现出很强的荧光发射。荧光显微镜成像和二次离子质谱成像（ToF-SIMS）的亚细胞分布研究表明，配合物 3 主要定位于细胞质，配合物 4 主要定位于细胞核。与 ctDNA 的竞争结合表明，配合物 4 比配合物 3 更有利于与 DNA 小沟结合。这些差异表明，配合物 3 可能主要通过光诱导的 O 生成发挥其抗癌活性，而配合物 4 则通过与 DNA 结合发挥作用。
