Caruso Francesco, Pettinari Riccardo, Rossi Miriam, Monti Elena, Gariboldi Marzia Bruna, Marchetti Fabio, Pettinari Claudio, Caruso Alessio, Ramani Modukuri V, Subbaraju Gottumukkala V
Vassar College, Department of Chemistry, Poughkeepsie, NY 12604, USA.
School of Science and Technology, Università di Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
J Inorg Biochem. 2016 Sep;162:44-51. doi: 10.1016/j.jinorgbio.2016.06.002. Epub 2016 Jun 4.
The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC are halved. Therefore, after replacing OH curcumin groups with OCH, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity.
本文描述了含有修饰姜黄素配体（HCurcI =(1E,4Z,6E)-5-羟基-1,7-双(3,4-二甲氧基苯基)庚-1,4,6-三烯-3-酮和HCurcII =(1E,4Z,6E)-5-羟基-1,7-双(4-甲氧基苯基)庚-1,4,6-三烯-3-酮）的钌(II)芳烃（对异丙基苯、苯、六甲基苯）衍生物的抗肿瘤活性。这些衍生物已通过红外光谱、电喷雾电离质谱和核磁共振光谱进行了表征。已测定了HCurcI的X射线晶体结构，并与其相关的钌配合物进行了比较。对四种配合物针对五种肿瘤细胞系进行了评估，其最佳活性[IC（μM）]分别为：乳腺癌MCF7，9.7；卵巢癌A2780，9.4；胶质母细胞瘤U-87，9.4；肺癌A549，13.7；结肠直肠癌HCT116，15.5；它们与凋亡特征相关。与已知的相应姜黄素配合物（对异丙基苯）Ru（姜黄素）Cl相比，这些活性有所提高，在乳腺癌和卵巢癌中约提高了两倍，在肺癌中强4.7倍，在胶质母细胞瘤细胞系中强约6.6倍。事实上，活性较低的（对异丙基苯）Ru（姜黄素）Cl配合物在结肠癌细胞系中仅表现出与两种新型配合物相似的活性。比较这些新型配合物与其相关姜黄素类化合物之间的抗肿瘤活性，在A2780、A549和U87细胞系中，含有CurcII的配合物的抗增殖活性有所提高，其IC值减半。因此，用甲氧基取代姜黄素的羟基后，所得的HCurcI及其钌配合物与姜黄素及其相关配合物相比，抗肿瘤活性有所增加。相比之下，HCurcII的细胞毒性低于姜黄素，但其相关配合物[（对异丙基苯）Ru（CurcII）Cl]在3种细胞系中的活性是HCurcII的两倍。这些新型芳烃-钌姜黄素类化合物的结果表明，它们对肿瘤细胞的细胞毒性增加与姜黄素类化合物亲脂性的增加相关。
