MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
Chemistry. 2013 Jul 29;19(31):10160-9. doi: 10.1002/chem.201300814. Epub 2013 Jul 4.
Histone deacetylases inhibitors (HDACis) have gained much attention as a new class of anticancer agents in recent years. Herein, we report a series of fluorescent ruthenium(II) complexes containing N(1)-hydroxy-N(8)-(1,10-phenanthrolin-5-yl)octanediamide (L), a suberoylanilide hydroxamic acid (SAHA) derivative, as a ligand. As expected, these complexes show interesting chemiphysical properties, including relatively high quantum yields, large Stokes shifts, and long emission lifetimes. The in vitro inhibitory effect of the most effective drug, Ru(DIP)2L2 (3; DIP: 4,7-diphenyl-1,10-phenanthroline), on histone deacetylases (HDACs) is approximately equivalent in activity to that of SAHA, and treatment with complex 3 results in increased levels of the acetylated histone H3. Complex 3 is highly active against a panel of human cancer cell lines, whereas it shows relatively much lower toxicity to normal cells. Further mechanism studies show that complex 3 can elicit cell cycle arrest and induce apoptosis through mitochondria-related pathways and the production of reactive oxygen species. These data suggest that these fluorescent ruthenium(II)-HDACi conjugates may represent a promising class of anticancer agents for potential dual imaging and therapeutic applications targeting HDACs.
近年来，组蛋白去乙酰化酶抑制剂（HDACi）作为一类新型的抗癌药物备受关注。在此，我们报告了一系列含有 N(1)-羟基-N(8)-(1,10-菲咯啉-5-基)辛二酰胺（L）的荧光钌（II）配合物，L 是一个琥珀酰亚胺基羟肟酸（SAHA）衍生物，作为配体。正如预期的那样，这些配合物表现出有趣的物理化学性质，包括相对较高的量子产率、较大的斯托克斯位移和较长的发射寿命。最有效的药物 Ru(DIP)2L2（3；DIP：4,7-二苯基-1,10-菲咯啉）对组蛋白去乙酰化酶（HDACs）的体外抑制作用与 SAHA 相当，且用复合物 3 处理会导致乙酰化组蛋白 H3 的水平增加。复合物 3 对一组人类癌细胞系具有高度活性，而对正常细胞的毒性相对较低。进一步的机制研究表明，复合物 3 可以通过线粒体相关途径和活性氧的产生引起细胞周期停滞和诱导细胞凋亡。这些数据表明，这些荧光钌（II）-HDACi 缀合物可能代表一类有前途的抗癌药物，可用于针对 HDACs 的潜在双重成像和治疗应用。
