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

Abstract

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.

Dual Functional Half‐Sandwich Ru(II) Complexes: Lysosome‐Targeting Probes and Anticancer Agents

“…Ru2 displayed higher hydrophobicity and the most antiproliferative activity than Ru1 and Ru3 . Similarly, the same trend that the cytotoxicity of the respective complexes tend to correlate with the observed lipophilicity that they provide reported by Dyson …”

“…Notably, Ru2 demonstrated 4.9‐fold greater potency after 72 h incubation than that after 24 h incubation in A549 cells and approximately 1.6‐fold greater potency than cisplatin. Previous cytotoxicity studies on ruthenium(II) p ‐cymene anticancer complexes show that a marked increase in the cytotoxicity when aspirin and valproic acid was introduced on α‐diimine ligands . The resulting IC 50 values showed that substitution of the alterations to the chelating ligand had minimal effect on inhibitory activity in this study.…”

“…These agents not only showed rich redox chemistry (Ru II and Ru III ) but also had less toxicity than their platinum analogs . A recent study by Dyson has shown that ruthenium arene complexes containing α‐diimine ligands have appeared as potential anticancer agents . Previous investigators have demonstrated that ruthenium compounds have displayed potent anticancer activities, such as three ruthenium complexes (NAMI‐A, KP1019, and KP1339) and have entered clinical trials , .…”

Anticancer Potential of Diiron Vinyliminium Complexes

“…Octanol‐water partition coefficients (Log P ow , see Table ) of [ 2 – 19 ]CF 3 SO 3 were assessed spectrophotometrically using the shake‐flask method (see Experimental Section for details) . The majority of compounds display an amphiphilic character (−0.5<Log P ow <0.5), with the dimethyl‐iminium derivatives [ 2 – 10 ]CF 3 SO 3 being more hydrophilic than the N ‐Xyl complexes [ 11 – 18 ]CF 3 SO 3 .…”

Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study

“…For example, a host of ruthenium(II) p ‐cymene complexes containing a wide range of ligands, including α‐diimine ligands, imine‐pyridine ligands, and pyridine‐N‐heterocyclic carbene (NHC) ligands, has been developed with the aim of improving their anticancer properties (Scheme ) . Marchetti and co‐workers developed a series of water‐soluble ruthenium(II) p ‐cymene complexes containing different α‐diimine ligands ( I , Scheme ) . The cytotoxicity of these complexes strongly depended on the nature of the α‐diimine N ‐substituents.…”