Impact of the Halogen Substitution Pattern on the Biological Activity of Organoruthenium 8‑Hydroxyquinoline Anticancer Agents

8-Hydroxyquinoline and its derivatives have a broad variety of pharmacological properties, which make them an ideal bioactive building block in the development of metal-based anticancer drugs. In this account we aimed to rationalize the antiproliferative efficacy of organoruthenium compounds featuring 8-hydroxyquinoline-derived ligands and to elucidate structural determinants by using biological assays and bioanalytical methods. By systematically varying the halide substitution pattern at the 5- and 7-positions of the 8-hydroxyquinoline ligand, as well as the halido leaving group, a series of 5,7-dihalido-8-hydroxyquinoline Ru^II(η⁶-<i>p</i>-cymene) complexes were obtained. Studies on their cytotoxic activity revealed the minor impact of the substitution pattern (with the exception of complexes of 8-hydroxyquinoline) on their activity. Notably, the cellular accumulation showed no correlation with the cytotoxic activity, while the nature of the halido leaving group only had a significant influence in the case of the 8-hydroxyquinoline organoruthenium compounds. However, the compounds were shown to be very stable under a wide variety of pH conditions, making them possible candidates for further development as orally active anticancer agents

Impact of the Halogen Substitution Pattern on the Biological Activity of Organoruthenium 8‑Hydroxyquinoline Anticancer Agents

8-Hydroxyquinoline and its derivatives have a broad variety of pharmacological properties, which make them an ideal bioactive building block in the development of metal-based anticancer drugs. In this account we aimed to rationalize the antiproliferative efficacy of organoruthenium compounds featuring 8-hydroxyquinoline-derived ligands and to elucidate structural determinants by using biological assays and bioanalytical methods. By systematically varying the halide substitution pattern at the 5- and 7-positions of the 8-hydroxyquinoline ligand, as well as the halido leaving group, a series of 5,7-dihalido-8-hydroxyquinoline Ru^II(η⁶-<i>p</i>-cymene) complexes were obtained. Studies on their cytotoxic activity revealed the minor impact of the substitution pattern (with the exception of complexes of 8-hydroxyquinoline) on their activity. Notably, the cellular accumulation showed no correlation with the cytotoxic activity, while the nature of the halido leaving group only had a significant influence in the case of the 8-hydroxyquinoline organoruthenium compounds. However, the compounds were shown to be very stable under a wide variety of pH conditions, making them possible candidates for further development as orally active anticancer agents

Anticancer Ruthenium(η⁶‑<i>p</i>‑cymene) Complexes of Nonsteroidal Anti-inflammatory Drug Derivatives

Oxicams are a versatile family of heterocyclic compounds, and the two representatives meloxicam and piroxicam are widely used drugs for the treatment of a variety of inflammatory and rheumatic diseases in humans. As cancer-associated inflammation is known to occur in carcinogenesis, we aimed to combine compounds carrying bioactive oxicam moieties with ruthenium­(arene) fragments, known for anticancer activity. Ru^II(arene) complexes with methyl ester derivatives of the oxicam scaffold were prepared and characterized by standard methods and crystallographically. The organoruthenium compounds formed from Ru^II(η⁶-<i>p</i>-cymene) chlorido moieties and oxicam-based ligands were subjected to bioanalytical investigations to establish their physicochemical properties with regard to stability in DMSO and water as well as reactivity toward the amino acids l-histidine (His), l-methionine (Met), and l-cysteine (Cys) and the DNA model compound guanosine 5′-monophosphate (5′-GMP). The compounds hydrolyzed rapidly in water to give the respective aqua complexes, formed amino acid complexes with Met and His, but decompose with Cys, while interaction with 5′-GMP was through its phosphate residue. The anticancer activity of the complexes against the colon carcinoma HCT116 and breast cancer MDA MB 231 cancer cell lines was established using an <i>in vitro</i> assay. The cytotoxicity was found strongly dependent on the lipophilicity of the compound, as was shown through correlation with log<i> k</i>_w and clog<i> P</i> values of the ligands. The most lipophilic compound [chlorido­(methyl 4-oxido-2-benzyl-2<i>H</i>-1,2-benzothiazine-3-carboxylate-1,1-dioxide)­(η⁶-<i>p</i>-cymene)­ruthenium­(II)] was the most active in the cell assays, with an IC₅₀ of 80 μM in HCT116 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

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay

Exploration of a Series of 5‑Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure–activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed <i>T</i>_1/2 values of 1.1–1.2 h (dose of 5 mg/kg iv) and MTDs of 60–80 mg/kg (ip)

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