Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2‑<i>c</i>]quinolinePiperazine Hybrids

In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline–piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline–piperazine hybrids L^1–3 were prepared <i>in situ</i> and isolated as six ruthenium and osmium complexes [(η⁶-<i>p</i>-cymene)­M­(L^1–3)­Cl]­Cl, where L¹ = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-2-<i>N</i>-amine, M = Ru ([<b>1a</b>]­Cl), Os ([<b>1b</b>]­Cl), L² = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-4-<i>N</i>-amine, M = Ru ([<b>2a</b>]­Cl), Os ([<b>2b</b>]­Cl), L³ = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-8-<i>N</i>-amine, M = Ru ([<b>3a</b>]­Cl), Os ([<b>3b</b>]­Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV–vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [<b>1a</b>,<b>b</b>]­Cl–[<b>3a,b</b>]Cl was examined <i>in vitro</i> and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([<b>2a</b>]Cl and [<b>2b</b>]­Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure–activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline–piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-<i>c</i>]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

The synthesis of new modified indolo[3,2-<i>c</i>]quinoline ligands <b>L</b>^<b>1</b>−<b>L</b>^<b>8</b> with metal-binding sites is reported. By coordination to ruthenium− and osmium−arene moieties 16 complexes of the type [(η⁶-<i>p</i>-cymene)M(L)Cl]Cl (<b>1a</b>,<b>b</b>−<b>8a</b>,<b>b</b>), where M is Ru^II or Os^II and L is <b>L</b>^<b>1</b>−<b>L</b>^<b>8</b>, have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV−vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (<b>2a</b>,<b> 4a</b>,<b> 4b</b>,<b> 5a</b>,<b> 7a</b>, and <b>7b</b>). The complexes were tested for antiproliferative activity <i>in vitro</i> in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung cancer), yielding IC₅₀ values in the submicromolar or low micromolar range

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