α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p-Cymene Anticancer Complexes

被引:53
|
作者
Biancalana, Lorenzo [1 ]
Batchelor, Lucinda K. [2 ]
Funaioli, Tiziana [1 ]
Zacchini, Stefano [3 ]
Bortoluzzi, Marco [4 ]
Pampaloni, Guido [1 ]
Dyson, Paul J. [2 ]
Marchetti, Fabio [1 ]
机构
[1] Univ Pisa, Dipartimento Chim & Chim Ind, Via G Moruzzi 13, I-56124 Pisa, Italy
[2] Ecole Polytech Fed Lausanne, Inst Sci & Ingn Chim, CH-1015 Lausanne, Switzerland
[3] Univ Bologna, Dipartimento Chim Ind Toso Montanari, Viale Risorgimento 4, I-40136 Bologna, Italy
[4] Univ Ca Foscari Venezia, Dipartirnento Sci Mol & Nanosistemi, Via Torino 155, I-30170 Venice, Italy
基金
瑞士国家科学基金会;
关键词
INHIBITOR VALPROIC ACID; ARENE COMPLEXES; HUMAN OVARIAN; IN-VITRO; CONDUCTIVITY MEASUREMENTS; GLYOXAL DERIVATIVES; COORDINATION MODES; ANTITUMOR-ACTIVITY; PHASE I; METAL;
D O I
10.1021/acs.inorgchem.8b00882
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
alpha-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 a-diimine ligands, [(eta(6)-p-cymene)RuCl{kappa N-2-(HCNR)(2)}]NO3 (R = Cy, [1]NO3; R = 4-C6H10OH, [2]NO3; R = 4-C6H4OH, [3]NO3), were prepared in near-quantitative yields as their nitrate salts. [2]NO3 displays high water solubility. The potential of the a-diimine ligand in [3]NO3 as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(eta(6)-p-cymene)RuCl{kappa N-2-(HCN(4-C6H4OCO-R))(2})]NO3 (R = aspirinate, [5]NO3; valproate, [6]NO3) 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]NO3. 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 adiimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple a-diimine ligands ranging from inactive to IC50 values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO3 and [6]NO3, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO3.
引用
收藏
页码:6669 / 6685
页数:17
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