1,3-Dioxoindan-2-carboxamides as Bioactive Ligand Scaffolds for the Development of Novel Organometallic Anticancer Drugs

A series of novel 1,3-dioxoindan-2-carboxamide-based complexes were synthesized, designed to employ both the attributes of half-sandwich complexes and the topoisomerase inhibiting properties of the ligand scaffold. The compounds were characterized with standard analytical methods. Their stability in aqueous systems and the impact of either the metal center or the ligand scaffold on the affinity toward small biomolecules such as amino acids, DNA model compounds, and small proteins were determined by IT-ESI mass spectrometry. The cytotoxicity was investigated in three human cancer cell lines by means of a colorimetric MTT assay, and preliminary structure–activity relationships were derived. The benzyl derivatives showed the highest in vitro activity and promising topoisomerase IIα inhibition in the range of the IC₅₀ values. In addition, the induced changes in the cell cycle distribution were determined and the apoptosis induction potential elucidated

Data_Sheet_1_Novel 3-Hydroxy-2-Naphthoate-Based Task-Specific Ionic Liquids for an Efficient Extraction of Heavy Metals.DOCX

<p>Ionic liquids (ILs) are per definition salts with melting points below 100°C and might be green alternatives for the extraction of heavy metals from aqueous solutions due to their favorable environmental and physico-chemical properties. Partial solution during extraction, so-called leaching, however, limits their applicability. The present study synthesizes three novel ammonium and phosphonium ILs based on 3-hydroxy-2-naphthoic acid—trihexyltetradecylphosphonium—([P₆₆₆₁₄]), methyltrioctylphosphonium—([P₁₈₈₈]), and methyltrioctylammonium 3-hydroxy-2-naphthoate ([N₁₈₈₈][HNA])—by a deprotonation-metathesis route. The aims were to improve stability during extraction while still achieving high selectivity toward heavy metal ions, as well as to study the impact of different alkyl chains and the central atom of the cation on physico-chemical properties, extraction efficacy, and leaching. Extraction capabilities for the seven heavy metals Ag, Cd, Co, Cu, Mn, Ni, and Pb were studied in pure water at pH 8.0. Further experiments were conducted in water containing 30 g L⁻¹ NaCl to simulate a seawater matrix and/or 30 mg L⁻¹ humic acids, as well as metal-spiked natural water samples. All three ILs showed extraction efficacies ≥90% for Cu and Pb after 24 h. Overall, extraction efficacies for Ag, Cd, Cu, and Pb were highest for drinking water samples. Ag and Cd extraction was increased by up to 41% in (hyper-) saline samples using IL [P₆₆₆₁₄][HNA] compared with pure water samples. Leaching values were reduced down to 0.07% loss of the applied IL, which can be attributed to the hydrophobic character of 3-hydroxy-2-naphthoate. Our results represent a positive development toward a greener extraction of heavy metals from natural waters.</p

1,3-Dioxoindan-2-carboxamides as Bioactive Ligand Scaffolds for the Development of Novel Organometallic Anticancer Drugs

A series of novel 1,3-dioxoindan-2-carboxamide-based complexes were synthesized, designed to employ both the attributes of half-sandwich complexes and the topoisomerase inhibiting properties of the ligand scaffold. The compounds were characterized with standard analytical methods. Their stability in aqueous systems and the impact of either the metal center or the ligand scaffold on the affinity toward small biomolecules such as amino acids, DNA model compounds, and small proteins were determined by IT-ESI mass spectrometry. The cytotoxicity was investigated in three human cancer cell lines by means of a colorimetric MTT assay, and preliminary structure–activity relationships were derived. The benzyl derivatives showed the highest in vitro activity and promising topoisomerase IIα inhibition in the range of the IC₅₀ values. In addition, the induced changes in the cell cycle distribution were determined and the apoptosis induction potential elucidated

Physicochemical Studies and Anticancer Potency of Ruthenium η⁶-<i>p</i>-Cymene Complexes Containing Antibacterial Quinolones

With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (<b>2</b>) and cinoxacin (<b>3</b>) were synthesized, and their physicochemical properties were compared to those of chlorido(η⁶-<i>p</i>-cymene)(ofloxacinato-κ²<i>O</i>,<i>O</i>)ruthenium(II) (<b>1</b>). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. <b>2</b> and <b>3</b> are significantly more stable than <b>1</b> and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)₃Ru(cym)]⁺ species (cym = η⁶-<i>p</i>-cymene). In the presence of human serum albumin <b>1</b>−<b>3</b> form adducts with this transport protein within 20 min of incubation. With guanosine 5′-monophosphate (5′-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for <b>1</b> in CH1 ovarian cancer cells, whereas <b>2</b> and <b>3</b> turned out to be inactive

Synthesis and Biological Evaluation of the Thionated Antibacterial Agent Nalidixic Acid and Its Organoruthenium(II) Complex

The thionated derivative of the antibacterial agent nalidixic acid and its organoruthenium complex were prepared, and their crystal structures were determined. The aqueous stability of the complex was studied and, unlike the case for the nalidixicato complex, increased stability of the ruthenium complex in aqueous solution was observed with only a minor degree of thionalidixicato ligand dissociated within 1 week. While the derivatization caused the antibacterial activity of the ligand against E. coli to decrease, the cytotoxicity of the complex against three cancer cell lines was significantly increased and the inhibitory potency against two enzymes of the cathepsin family was increased by 10-fold

Introducing the 4‑Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates

Herein we report the synthesis, anticancer potency <i>in vitro</i>, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium­(II) (<b>2a</b>–<b>e</b>) and osmium­(II) (<b>3a</b>–<b>e</b>) organometallics of the general form [(η⁶-<i>p</i>-cym)­RuCl­(κ²-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure–activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC₅₀ values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium­(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium­(II) counterparts. The IC₅₀ values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives <b>2b</b> and <b>3b</b> showed pronounced effects on cell cycle distribution

Introducing the 4‑Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates

Herein we report the synthesis, anticancer potency <i>in vitro</i>, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium­(II) (<b>2a</b>–<b>e</b>) and osmium­(II) (<b>3a</b>–<b>e</b>) organometallics of the general form [(η⁶-<i>p</i>-cym)­RuCl­(κ²-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure–activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC₅₀ values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium­(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium­(II) counterparts. The IC₅₀ values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives <b>2b</b> and <b>3b</b> showed pronounced effects on cell cycle distribution

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