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.

A series of 11 novel ruthenium(ii) arene complexes [Ru(p-cym)(trzC^N)L]NO3 based on the cycloruthenated 1,2,3-triazole scaffold (trzC^N) bearing different N- or S-donor leaving groups (L) were prepared. These complexes exhibited strongly diverging pH-dependent stability profiles, but consistently exerted antiproliferative effects in the low micromolar range in three cancer cell lines (A549, SW480, CH1/PA-1). The interaction with biomolecules was correlated to dissociation of the monodentate leaving group. Under oxidative conditions, the stably bound dimethylsulfide ligand (3a) undergoes oxidation, while metal coordination is maintained, affording the labile DMSO complex (3b). Rationalization of the homogenous antiproliferative activities was attempted by determination of the cellular accumulation and lipophilicity indices (φ0). Investigations on their mechanism of action revealed that these metalacycles are inducers of apoptosis, exert a slight antioxidative effect in cell culture studies, but have no DNA intercalatory activity.

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