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

Organometallic 3-(1<i>H</i>-Benzimidazol-2-yl)-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines as Potential Anticancer Agents

Six organometallic complexes of the general formula [M^IICl(η⁶-<i>p</i>-cymene)(L)]Cl, where M = Ru (<b>11a</b>, <b>12a</b>, <b>13a</b>) or Os (<b>11b</b>, <b>12b</b>, <b>13b</b>) and L = 3-(1<i>H</i>-benzimidazol-2-yl)-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines (<b>L1</b>–<b>L3</b>) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV–vis spectroscopy, ESI mass spectrometry, and X-ray crystallography (<b>11b</b> and <b>12b</b>). The multistep synthesis of 3-(1<i>H</i>-benzimidazol-2-yl)-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines (<b>L1</b>–<b>L3</b>), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine-3-carboxylic acid (<b>3</b>) via 5-bromo-3-methyl-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine (<b>2</b>); the synthesis of 1-methoxymethyl-2,3-diaminobenzene (<b>5</b>) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine-3-carboxylic acids (<b>1</b>, <b>3</b>) through the use of an inexpensive coupling reagent, <i>N</i>,<i>N</i>′-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted <b>L3</b> by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b-<b>L3</b> and 4b′-<b>L3</b> in a metal-free state are described. Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported

A SAR Study of Novel Antiproliferative Ruthenium and Osmium Complexes with Quinoxalinone Ligands in Human Cancer Cell Lines

A series of ruthenium­(II) arene complexes with 3-(1<i>H</i>-benzimidazol-2-yl)-1<i>H</i>-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV–vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC₅₀ values of 6–60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate

Structure–Activity Relationships of Targeted Ru^II(η⁶‑<i>p</i>‑Cymene) Anticancer Complexes with Flavonol-Derived Ligands

Ru^II(arene) complexes have been shown to be promising anticancer agents, capable of overcoming major drawbacks of currently used chemotherapeutics. We have synthesized Ru^II(η⁶-arene) compounds carrying bioactive flavonol ligands with the aim to obtain multitargeted anticancer agents. To validate this concept, studies on the mode of action of the complexes were conducted which indicated that they form covalent bonds to DNA, have only minor impact on the cell cycle, but inhibit CDK2 and topoisomerase IIα in vitro. The cytotoxic activity was determined in human cancer cell lines, resulting in very low IC₅₀ values as compared to other Ru^II(arene) complexes and showing a structure–activity relationship dependent on the substitution pattern of the flavonol ligand. Furthermore, the inhibition of cell growth correlates well with the topoisomerase inhibitory activity. Compared to the flavonol ligands, the Ru^II(η⁶-<i>p</i>-cymene) complexes are more potent antiproliferative agents, which can be explained by potential multitargeted properties