Ruthenium tetrazene complexes bearing glucose moieties on their periphery: Synthesis, characterization, and in vitro cytotoxicity

Abstract

Ruthenium tetrazene complexes with general formula [Cp*RuCl(1,4-R 2 N 4)] (Cp* = η 5-C 5 Me 5), where R = benzyl (1), 2-fluorobenzyl (2), β-D-glucopyr anosyl-unprotected (3a) and acyl-protected (3b-d), 2-acetamido-β-Dglucopyranosyl-unprotected (4a) and acyl-protected (4b-d), propyl-β-D-glucopyranoside-unprotected (5a), and O-acetylated (5b), were synthesized and characterized using nuclear magnetic resonance and electrospray ionizationmass spectrometry. In addition, the molecular structure of 3b was determined using X-ray crystallography. The cytotoxicity of complexes against ovarian (A2780, SK-OV-3) and breast (MDA-MB-231) cancer cell lines and noncancerous cell line HEK-293 was evaluated and compared to cisplatin activity. The carbohydrate-modified complexes bearing acyl-protecting groups exhibited higher efficacy (in low micromolar range) than unprotected ones, where the most active 4d was superior to cisplatin up to five times against all investigated cancer cell lines; however, no significant selectivity was achieved. The complex induced apoptotic cell death at low micromolar concentrations (0.5 μM for A2780 and HEK293; 2 μM for SK-OV-3 and MDA-MB-231). K E Y W O R D S anticancer activity, glucose derivatives, ruthenium complexes, tetrazene ligands V. Hamala and A. Martišová contributed equally to this study.

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

“…Changing the O -benzoyl groups to smaller O -acetyl groups ( Ru-4 vs. Ru-5 ) or complete deprotection ( Ru-4 vs. Ru-10 ) abrogated the inhibitory activity. These findings are similar to the observations of Hamala and colleagues [ 22 ], who showed that the inhibitory activity of carbohydrate-based ruthenium complexes ( Figure 1 , X ) was enhanced when the hydroxyl groups of the sugar units were protected by esters. Furthermore, increasing the length of the acyl chain improved the inhibitory efficacy (acetyl < propionyl < butyryl).…”

“…The activity of the compounds was dependent on the presence of ruthenium(II), as the ligands had no biological activity. The IC 50 values of the active compounds were comparable or superior to the currently applied platinum compounds (cisplatin, oxaliplatin, and carboplatin) and other sugar-containing ruthenium complexes [ 22 , 23 , 52 , 53 ]. The identified Ru(II) compounds were active upon long-term application in SRB assays, similar to platinum compounds.…”

“…Prior studies [ 22 , 23 , 52 , 53 ] have suggested that sugar-based ruthenium complexes may be active on other cell lines and, therefore, potentially in other neoplastic diseases. We assessed breast cancer (modelled by MCF7 cells) as prior data [ 22 ] suggested the potential effectiveness of ruthenium complexes.…”

“…Prior studies [ 22 , 23 , 52 , 53 ] have suggested that sugar-based ruthenium complexes may be active on other cell lines and, therefore, potentially in other neoplastic diseases. We assessed breast cancer (modelled by MCF7 cells) as prior data [ 22 ] suggested the potential effectiveness of ruthenium complexes. Pancreatic adenocarcinoma (modelled by Capan2 cells) and glioblastoma (modelled by U251 cells), similar to ovarian cancer, are usually malign diseases where treatment options are limited [ 54 , 55 , 56 ].…”

“…For several sugar-containing half-sandwich Ru(II) complexes, such as RAPTA analogs with glycofuranose-based phosphite ligands [ 15 ] ( VIII ) and Ru(II) complexes having 2,3-diamino-2,3-dideoxy-hexopyranoside [ 21 ] ( IX ) or 1,4-bis(β- d -glycopyranosyl)tetrazene-type N,N -chelating ligands [ 22 ] ( X ), the antiproliferative activity has already been justified. In addition, certain cyclopentadienyl-ruthenium(II) complexes with sugar-based heterocyclic mono- ( XI , XII ) or bidentate ligands ( XIII ) have also been shown to display low micromolar cytotoxic activity in human cervical carcinoma (HeLa) and colon cancer HCT116 cell lines [ 23 , 24 , 25 ].…”