Tumor-inhibiting metal complexes with naphthoquinone-derived ligands

Metallhältige Zytostatika sind in der Chemotherapie von großer Bedeutung. Die bekanntesten Verbindungen dieser Art sind die Platinkomplexe Cisplatin, Carboplatin und Oxaliplatin, welche jedoch ein breites Spektrum an Nebenwirkungen (Nephrotoxizität, Übelkeit, Erbrechen, Nervenschäden, etc.) aufweisen. Um diese nachteiligen Effekte zu umgehen, wird an der Entwicklung von neuen Krebstherapeutika geforscht, wobei Komplexverbindungen mit Ruthenium als Zentralatom von großem Interesse sind. Die Ruthenium(III)-Komplexe NAMI-A und KP1019 sind in klinischen Studien und in ihrer Entwicklung am weitesten vorangeschritten. Man nimmt an, dass die aktive Spezies erst durch intrazelluläre Reduktion von Ru(III) zu Ru(II) generiert wird („Activation by Reduction – Hypothese“ von Clarke), und dass der Transport im wesentlichen durch Plasmaproteine nach intravenöser Administration erfolgt. Seit einigen Jahren schreitet die Entwicklung in Richtung organometallischer Chemotherapeutika stark voran. Solche Ru(II) Verbindungen weisen eine sog. „piano-stool“ – Konfiguration auf, wobei der Einfluss des Arenliganden bereits eingehend untersucht wurde. Für die restlichen drei Bindungsstellen werden überwiegend zweizähnige Chelatliganden und ein Halogenidoligand verwendet. Diese Art von Verbindung ermöglicht ein sehr genaues Design von Substanzen mit spezifischen Eigenschaften. Diese umschließen sowohl biophysikalische Eigenschaften, wie die Löslichkeit und Lipophilie, aber auch die Reaktivität zu Biomolekülen oder auch die Wechselwirkung mit Biomolekülen durch Bindung in spezifische Enzymbindungsstellen. 2-Hydroxy-1,4-naphthochinonliganden sind eine Weiterentwicklung der bereits bekannten Pyron-basierten Chelatliganden (4-Pyron, Kojisäure, Maltol, Allomatol, etc.). Bei Koordination an Metallzentren bleibt die erste Koordinationssphäre unverändert. Aufgrund des chinoiden Systems könnten jedoch intrazellulär reaktive Sauerstoffspezies generiert und damit Verbindungen mit neuen Eigenschaften und verbesserter Antitumoraktivität erzielt werden. Weiters ist bekannt, dass einige Naphthochinonderivate Enzyme der Cdc25 Familie inhibieren können. So könnten möglicherweise auch über diesen Weg, verbesserte zytostatische Eigenschaften der Substanzen erreicht werden. Im Rahmen meiner Masterarbeit wurden nun Aren-Komplexe mit verschiedenen 2-Hydroxy-1,4-naphthochinon Liganden hergestellt und charakterisiert.Metal containing cytostatics are very important in cancer treatment. The most prominent compounds of this kind are the platinum drugs cisplatin, carboplatin and oxaliplatin. A big disadvantage of these complexes is a broad spectrum of side effects, like nephrotoxicity, vomiting, nausea, neurotoxicity and so on. To avoid these adverse effects, the research for new chemotherapeutics focused on metal complexes with other central atoms than platinum(II). The ruthenium(III) complexes NAMI-A and KP1019 are under clinical trials and show promising results. It is assumed, that the reactive species are generated through intracellular reduction from Ru(III) to Ru(II) (“activation by reduction-hypothesis” by Clarke). The transport occurs through binding to plasma proteins after intravenous application. Since a few years, organometallic chemotherapeutics are under intensive investigation. Such Ru(II) compounds have a so called “piano-stool” configuration and the influence of the arene moiety on the biological activity was already extensively studied. For the remaining three binding sites bidentate ligands and one halido ligand are most frequently used. This type of coordination compound allows to tune the properties of the substance. This includes biophysical properties such as solubility and lipophilicity, but also the reactivity against biomolecules, or interaction with different biomolecules through binding to enzyme binding sites. 2-Hydroxy-[1,4]-naphthoquinone ligands exhibit the same first coordination sphere as the well-studied (thio)pyr(id)one-based metal complexes (4-pyrone, kojic acid, maltol, allomaltol, etc.).. Due to the quinonoid system, reactive oxygen species may be generated, which could lead to compounds with new properties and improved antitumor activity. Furthermore it is known, that some naphthoquinone derivatives inhibit enzymes of the cdc25 family, which could be another mode of action for improved cytostatic properties. In my master thesis Ru(II) and Os(II) arene-complexes with different 2-hydroxy-[1,4]-naphthoquinones as chelating ligands were synthesized and characterized

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

Structural Modifications of the Antiinflammatory Oxicam Scaffold and Preparation of Anticancer Organometallic Compounds

Nonsteroidal antiinflammatory drugs (NSAIDs) have chemopreventive effects in several cancer types, and the oxicam-based NSAIDs meloxicam and piroxicam exhibit potential to treat cancer. We prepared a series of novel oxicams and coordinated them to RuII(cym)Cl and OsII(cym)Cl moieties (η6-p-cymene = cym). The oxicam ligands acted either as monodentate N-donors or bidentate N,O-chelators, depending upon the ligand structure as well as reaction conditions such as the pH value and solvent used in the reaction. The cytotoxic activity of the complexes toward carcinoma cells was investigated. The isoxazolyl motif-containing ligand 1 and its complexes with RuII­(cym)Cl 1a and the Os analogue 1b proved to have anticancer activity with IC50 values in a range similar to that observed for the RuIII investigational drug IT-139, and in general the Os compounds were equally or even slightly more potent than the Ru derivatives. Since meloxicam is known as a selective inhibitor of COX-2, molecular docking studies were carried out to understand the possible interactions of the compounds with COX-2, where the organic ligands gave higher scores than their organometallic counterparts

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