Hoch zytotoxische Kupfer(II)-Komplexe modifizierter Paullon-Liganden

Krebserkrankungen stellen heute die zweithäufigste Todesursache in Österreich und bereits die dritthäufigste weltweit dar. Dem entsprechend hat sich auch die Krebsfor-schung weiterentwickelt. Zu den heute angewandten Standardtherapien zählt neben Chirurgie und Strahlentherapie vor allem die Chemotherapie. Beinahe die Hälfte der Krankheitsfälle wird mit den platinhältigen Medikamenten Cisplatin, Carboplatin und Oxaliplatin behandelt. Die auftretenden Nebeneffekte wie Nephro- und Neurotoxizi-tät, Übelkeit und Erbrechen zählen zu ihren großen Nachteilen. Zusätzlich können im Verlauf der Behandlung Resistenzen gegen die Therapeutika auftreten. Darum kon-zentriert sich die Forschung zunehmend auf die Entwicklung von Medikamenten, die auf anderen Metallionen basieren, um den auftretenden Nachteilen platinhältiger Medikamente entgegenzuwirken. Speziell die Komplexe der dreiwertigen Ionen des Galliums (z.B. KP46) und Rutheniums (z.B. NAMI-A, KP1019), die Eisen in biologi-schen Systemen nachahmen, zeigen vielversprechende antiproliferative Aktivität, obwohl sie weniger zytotoxisch sind als die bereits angewandten Platinverbindungen. Die Koordination biologisch aktiver Liganden an Metallionen ist ein ebenfalls vielver-sprechender Ansatz. Indolo[3,2-d][1]benzazepine (Paullone) hemmen Zyklin abhän-gige Kinasen (CDKs), Enzyme die den Zellzyklus kontrollieren. Speziell Kenpaullon ähnelt in seiner Aktivität Flavopiridol, einem bereits bekannten Inhibitor des CDK1-cyclinB Komplexes. Die geringe Bioverfügbarkeit der Paullone bleibt ein beschrän-kender Faktor. Die Koordination von Paullonderivaten als Liganden an Ruthenium und Osmium hat bereits zur Lösung des Problems beigetragen (höhere Löslichkeit in wässrigen Medien, höhere Zytotoxizität), aber da es sich bei Ruthenium und Osmium nicht um Spurenelemente handelt, wurde der Fokus auf Ionen von biokompatiblen Elementen der ersten Übergangsmetallreihe gerichtet. Ziel dieser Arbeit war die Synthese und Charakterisierung von Kupfer-Komplexen mit Paullonderivaten als Liganden, sowie Zytotoxizitätstests.Cancer diseases are the second most common cause of death in Austria and third worldwide. Therefore much attention has been given to cancer research and thera-pies over the last decades. Beside surgery and radiation therapy, chemotherapy is the most common treatment of cancer. In almost 50% of incidences the platinum based drugs cisplatin, carboplatin and oxaliplatin are used to cure the diseases. Re-lated side effects, such as nephrotoxicity, neurotoxicity, nausea, vomiting, etc. are the main disadvantages. A growing chemoresistance to these classical drugs is an-other stimulus to overcome these problems. Consequently the focus of researchers turned to other metal ions as coordination centres. Especially complexes of gal-lium(III) (e.g. KP46) and ruthenium(III) (e.g. NAMI-A, KP1019), which imitate the properties of iron in biological systems, show promising antiproliferative activities even though they are less cytotoxic than the platinum based drugs. Another promising approach to new chemotherapeutics is the coordination of biologi-cally active ligands to metal ions. Indolo[3,2-d][1]benzazepines (paullones) were found to be potent inhibitors of Cyclin dependent kinases (CDKs), enzymes control-ling the cell cycle progression. Especially Kenpaullone exhibits an activity profile simi-lar to Flavopiridol, which is a well known inhibitor of the CDK1-cyclinB complex. Nonetheless the poor bioavailability of the paullones remains a limiting factor for ap-plication. Coordination of paullone derivatives to ruthenium and osmium resulted in higher solubility in aqueous media and increased cytotoxicity. However, ruthenium and osmium are not essential trace elements. Therefore we focused our attention on complexes of the biocompatible first row transition metals. The aim of this work was the synthesis and characterisation of copper complexes of paullone-based ligands, their characterisation by available techniques and cytotoxic-ity tests with respect to the antiproliferative activity of the newly synthesised com-pounds

Conjugation of Organoruthenium(II) 3-(1H-Benzimidazol-2-yl)pyrazolo[3,4-b]pyridines and Indolo[3,2-d]benzazepines to Recombinant Human Serum Albumin: a Strategy To Enhance Cytotoxicity in Cancer Cells

Five organoruthenium complexes [RuCl(η6-arene)(L)]Cl with a modified arene ligand, namely, 4-formylphenoxyacetyl-η6-benzylamide, and L = 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines or indolo[3,2-d]benzazepines were synthesized and conjugated to recombinant human serum albumin in order to improve their drug targeting and delivery to cancer cells, and a marked increase in cytotoxicity was observed

Targeting the endoplasmic reticulum with a membrane-interactive luminescent ruthenium(II) polypyridyl complex

The characterization and bioactivity of the dinuclear ruthenium(II) complex [(Ru(DIP)2)2(tpphz)]4+ (DIP = 4,7-diphenyl-1,10-phenanthroline and tpphz = tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′′,3′′′-j]phenazine) is reported. This new complex is found to be luminescent in acetonitrile, where excitation into MLCT (metal-to-ligand charge-transfer) bands in the visible area of the spectrum (λex = 450 nm, ε = 45 000 M−1 cm−1) result in red emission (λem,max = 620 nm, ΦMLCT = 0.017). Aqueous in vitro binding studies indicate that this complex binds to duplex DNA with an affinity of 1.8 × 106 M−1 through a non-classical groove-binding interaction, however, unlike the parent complex [(Ru(phen)2)2(tpphz)]4+ (phen = 1,10-phenanthroline), it also displays an increase in MLCT luminescence on addition of liposomes. Confocal microscopy and TEM studies show that this lipophilic complex targets the endoplasmic reticulum of eukaryotic cells, where it functions as an imaging agent for this organelle, and cytotoxicity studies in human cancer cell lines indicate a comparable potency to the anti-cancer drug cisplatin

Dicopper(II) and Dizinc(II) Complexes with Nonsymmetric Dinucleating Ligands Based on Indolo[3,2- c ]quinolines: Synthesis, Structure, Cytotoxicity, and Intracellular Distribution

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Mechanical but not physical dormancy is a cause of poor germination in teak (Tectona grandis L.f.)

Poor seed germination is a significant problem for propagation of teak and it particularly hampers the deployment of genetically improved material into plantations. Seed dormancy is the putative cause for delayed and sporadic germination of teak seed but specific dormancy mechanisms have not been proven. In this paper we investigate whether physical or mechanical dormancy could affect teak germination. Physical dormancy was disproved when we observed water in every examined locule of fruit which had been immersed for 12–24 h (n = 1,700 fruits from six diverse sources). Mechanical dormancy was found to affect teak seed germination by means of valve structures which must open for the radicle to emerge. All 1,450 germinating seeds in 16 samples emerged from the endocarp via the detachment of a valve. Germination over 16 days was compared between extracted seeds (ex situ) and seeds within their endocarp (in situ) to determine the effect of mechanical dormancy on germination. Significantly greater germination of the ex situ seeds (62 ± 2% SE; n = 486) than of the in situ seeds (32 ± 2% SE; n = 564) indicated that mechanical dormancy is an important factor in the poor germination of teak

Highly Cytotoxic Copper(II) Complexes with Modified Paullone Ligands

The reaction of copper(II) chloride or copper(II) acetate with 6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo-[3,2-d][1]benzazepine (HL1), 9-bromo-6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (HL2), N-9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-methylidene)azine (HL3), or N-9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-ethylidene)azine (HL4) in methanol affords the novel copper(II) complexes [Cu(HL1)Cl2] (1), [Cu(HL2)Cl2] (2), [Cu(HL3)Cl2] (3), [Cu(HL4)Cl2] (4), and [Cu(L4)(CH3COO)(CH3OH)] (5). The new ligands (HL2 and HL3) and the complexes 1-5 were characterized by 1H and 13C NMR, IR and electronic absorption spectroscopy, ESI mass spectrometry, and X-ray crystallog. Two ligands, HL1 and HL2, and complexes 1-4 were tested for cytotoxicity in three human cancer cell lines, namely, CH1 (ovarian carcinoma), A549 (non-small cell lung cancer), and SW480 (colon carcinoma). Addnl., complexes 1, 2, and 4 were assayed in an isogenic pair of ovarian cancer cell lines, one being sensitive to cisplatin (A2780) and the other having acquired cisplatin resistance (A2780cisR). All of the compds. evaluated are cytotoxic, with complexes 3 and 4 exhibiting IC50 values in the nanomolar range