Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L1) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L2) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L3) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L4) of the general formulas [(η6-p-cymene)MII(L1)Cl]Cl, where M is Ru (4) and Os (6), [(η6-p-cymene)MII(L2)Cl]Cl, where M is Ru (5) and Os (7), [(η6-p-cymene)MII(L3)Cl]Cl, where M is Ru (8) and Os (10), and [(η6-p-cymene)MII(L4)Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L1·HCl, 4·H2O, 5, and 9·2.5H2O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC50 values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L1 and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L4 and 11, arguing for additional targets and molecular effects, such as intercalation into DNA

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

Anticancer Ruthenium(η6-p-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. RuII(arene) complexes with methyl ester derivatives of the oxicam scaffold were prepared and characterized by standard methods and crystallographically. The organoruthenium compounds formed from RuII(η6-p-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 in vitro assay. The cytotoxicity was found strongly dependent on the lipophilicity of the compound, as was shown through correlation with log kw and clog P values of the ligands. The most lipophilic compound [chlorido(methyl 4-oxido-2-benzyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide)(η6-p-cymene)ruthenium(II)] was the most active in the cell assays, with an IC50 of 80 μM in HCT116 cells

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

Metal–Arene Complexes with Indolo[3,2‑<i>c</i>]‑quinolines: Effects of Ruthenium vs Osmium and Modifications of the Lactam Unit on Intermolecular Interactions, Anticancer Activity, Cell Cycle, and Cellular Accumulation

Six novel ruthenium­(II)– and osmium­(II)–arene complexes with three modified indolo­[3,2-<i>c</i>]­quinolines have been synthesized in situ starting from 2-aminoindoloquinolines and 2-pyridinecarboxaldehyde in the presence of [M­(<i>p-</i>cymene)­Cl₂]₂ (M = Ru, Os) in ethanol. All complexes have been characterized by elemental analysis, spectroscopic techniques (¹H, ¹³C NMR, IR, UV–vis), and ESI mass spectrometry, while four complexes were investigated by X-ray diffraction. The complexes have been tested for antiproliferative activity in vitro in A549 (non-small cell lung), SW480 (colon), and CH1 (ovarian) human cancer cell lines and showed IC₅₀ values between 1.3 and >80 μM. The effects of Ru vs Os and modifications of the lactam unit on intermolecular interactions, antiproliferative activity, and cell cycle are reported. One ruthenium complex and its osmium analogue have been studied for anticancer activity in vivo applied both intraperitoneally and orally against the murine colon carcinoma model CT-26. Interestingly, the osmium­(II) complex displayed significant growth-inhibitory activity in contrast to its ruthenium counterpart, providing stimuli for further investigation of this class of compounds as potential antitumor drugs

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