Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates

Abstract

Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(η-p-cym)RuCl(κ-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution.

Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand

“…Overall, the results of cell cycle modifications revealed that the cellular effects of the Ru-dca complex are much more similar to the effects of cisplatin , while the Os-dca complex showed only a small effect on the cell cycle in the A2780 cells as compared to the negative control. Just for the comparative purposes we may show that similar human cancer cell cycle perturbations were recently reported for half-sandwich complexes [Ru(η 6 - p cym)(L 2 )Cl] and [Os(η 6 - p cym)(L 2 )Cl] containing 1-(4-methoxybenzyl)-4-phenyl-1 H -1,2,3-triazole (HL 2 ) [ 38 ].…”

Half-Sandwich Arene Ruthenium(II) and Osmium(II) Thiosemicarbazone Complexes: Solution Behavior and Antiproliferative Activity

“… 40 − 42 Investigations of osmium complexes as alternatives to ruthenium-based anticancer agents have resulted in structurally diverse libraries of osmium complexes with different oxidation states and nuclearity. 43 − 46 …”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[145] For several other Rubased compounds, there is some evidence [96,128,138] that they do not influence the immune response itself and might have synergistic effects in combination with cancer immunotherapy. [146] It is certain that RAPTA compounds do not induce the cancer immune response via thioredoxin levels and the regulation of the activity of thioredoxin reductase. [146] It is certain that RAPTA compounds do not induce the cancer immune response via thioredoxin levels and the regulation of the activity of thioredoxin reductase.…”