Structural Modifications of the Antiinflammatory Oxicam Scaffold and Preparation of Anticancer Organometallic Compounds

Nonsteroidal antiinflammatory drugs (NSAIDs) have chemopreventive effects in several cancer types, and the oxicam-based NSAIDs meloxicam and piroxicam exhibit potential to treat cancer. We prepared a series of novel oxicams and coordinated them to RuII(cym)Cl and OsII(cym)Cl moieties (η6-p-cymene = cym). The oxicam ligands acted either as monodentate N-donors or bidentate N,O-chelators, depending upon the ligand structure as well as reaction conditions such as the pH value and solvent used in the reaction. The cytotoxic activity of the complexes toward carcinoma cells was investigated. The isoxazolyl motif-containing ligand 1 and its complexes with RuII­(cym)Cl 1a and the Os analogue 1b proved to have anticancer activity with IC50 values in a range similar to that observed for the RuIII investigational drug IT-139, and in general the Os compounds were equally or even slightly more potent than the Ru derivatives. Since meloxicam is known as a selective inhibitor of COX-2, molecular docking studies were carried out to understand the possible interactions of the compounds with COX-2, where the organic ligands gave higher scores than their organometallic counterparts

High Antiproliferative Activity of Hydroxythiopyridones over Hydroxypyridones and Their Organoruthenium Complexes

Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a–1c and 3-hydroxy-4-thiopyridones 1d–1f as well as their Ru(η6-p-cymene)Cl complexes 2a–2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d–1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low μM range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells

(Pyridin-2-yl)-NHC Organoruthenium Complexes: Antiproliferative Properties and Reactivity toward Biomolecules

Organoruthenium compounds have been widely investigated for their anticancer activity. Here we use one of the classic ligand classes found in organometallics, i.e., N-heterocyclic carbenes (NHC), and coordinate them to the Ru­(η⁶-<i>p</i>-cymene) scaffold as <i>N</i>,<i>C</i>-bidentate ligands substituted with a pyridyl moiety. Introduction of different substituents gave compounds with a wide variety of properties. We investigated their stability in solution and in the presence of biomolecules, in vitro anticancer activity, and cellular uptake to rationalize their biological properties in dependence on the structure. A clear effect of their structure on the stability in water and DMSO was found for some derivatives, which was reflected in the reactivity to biomolecules that was determined with selected representatives of the compound classes. The antiproliferative activity of the compounds was widely dependent on the lipophilicity of the <i>N</i>,<i>C</i>-bidentate ligand, but as cellular accumulation studies revealed, lipophilicity does not provide the full picture and additional effects must be responsible for the anticancer activity

A Bioactive l‑Phenylalanine-Derived Arene in Multitargeted Organoruthenium Compounds: Impact on the Antiproliferative Activity and Mode of Action

Ru^II(η⁶-arene) compounds carrying bioactive flavonol ligands have shown promising anticancer activity against tumor cells via a multitargeting mode of action, i.e., through interaction with DNA and inhibition of topoisomerase IIα. By introducing a novel arene ligand based on the amino acid l-phenylalanine (Phe), we aimed to alter the pharmacological properties of the complexes. We report here a series of novel Ru^II(η⁶-arene)Cl complexes with different substituents on the phenyl ring of the flavonol which should maintain the multitargeting capability of the parent η⁶-<i>p</i>-cymene (cym) complexes. Studies with selected examples revealed stability in aqueous solution after quickly forming aqua complexes but rapid decomposition in pure DMSO. The reactions with protein and DNA models proceeded quickly and resulted in cleavage of the flavonol or adduct formation, respectively. The compounds were found to be cytotoxic with significant antiproliferative activity in cancer cells with IC₅₀ values in the low μM range, while not following the same trends as observed for the cym analogues. Notably, the cellular accumulation of the new derivatives was significantly higher than for their respective cym complexes, and they induced DNA damage in a manner similar to that of cisplatin but to a lesser extent

From Catalysis to Cancer: Toward Structure–Activity Relationships for Benzimidazol-2-ylidene-Derived <i>N</i>‑Heterocyclic-Carbene Complexes as Anticancer Agents

The promise of the metal­(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While <i>N</i>-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru^II(arene) pharmacophore and even less with an Os^II(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M–C_NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal–NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido­(1,3-dibenzylbenzimidazol-2-ylidene)­(η⁶-p-cymene)­ruthenium­(II) <b>1b</b>^<b>I</b> was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future