Dipartimento di Chimica e Chimica Industriale , Università di Pisa , Via G. Moruzzi 13 , I-56124 Pisa , Italy.
Institut des Sciences et Ingénierie Chimiques , Ecole Polytechnique Fédérale de Lausanne , CH-1015 Lausanne , Switzerland.
Inorg Chem. 2018 Jun 4;57(11):6669-6685. doi: 10.1021/acs.inorgchem.8b00882. Epub 2018 May 23.
α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η- p-cymene)RuCl{κ N-(HCNR)}]NO (R = Cy, [1]NO; R = 4-CHOH, [2]NO; R = 4-CHOH, [3]NO), were prepared in near-quantitative yields as their nitrate salts. [2]NO displays high water solubility. The potential of the α-diimine ligand in [3]NO as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η- p-cymene)RuCl{κ N-(HCN(4-CHOCO-R))}]NO (R = aspirinate, [5]NO; valproate, [6]NO) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1] with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO and [6]NO, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO.
α-二亚胺是合成配位化学中最强大和多功能的配体之一，具有可精细调节的空间和电子性质。一系列新型的阳离子钌（II）对伞花烃配合物，具有简单的α-二亚胺配体，[(η-对伞花烃)RuCl{κ N-(HCNR)}]NO（R = Cy，[1]NO；R = 4-CHOOH，[2]NO；R = 4-CHOOH，[3]NO），以近定量的产率作为它们的硝酸盐盐制备。[2]NO 具有高水溶性。通过与羟基的酯化反应，研究了[3]NO 中α-二亚胺配体作为生物活性分子载体的潜力。因此，双功能化衍生物[(η-对伞花烃)RuCl{κ N-(HCN(4-CHOCO-R))}]NO（R = 阿司匹林盐，[5]NO；丙戊酸盐，[6]NO）和[4]Cl（R = Me）也以良好至高的产率获得。在水溶液中的紫外可见和多核 NMR 光谱和循环伏安研究表明，只有少量的氯化钌水解断裂，可生物利用的还原电位，以及[3]NO 的 pH 依赖性行为。为了比较[1]中 Ru-Cl 键的强度与类似的乙二胺配合物，进行了密度泛函理论分析，表明在前者中观察到的更高稳定性与α-二亚胺配体的吸电子性质有关。进行了针对肿瘤（A2780 和 A2780cisR）和非肿瘤（HEK-293）细胞系的体外细胞毒性研究，具有简单α-二亚胺配体的配合物的范围从无活性到低微摩尔范围内的 IC 值。用生物活性成分（即[5]NO 和[6]NO）功能化的配合物与前体[3]NO 相比，细胞毒性明显增加。
