Time filter

Source Type

NavakoskideOliveira K.,TU Braunschweig | Andermark V.,TU Braunschweig | vonGrafenstein S.,University of Innsbruck | Onambele L.A.,Cologne Childrens Hospital | And 7 more authors.
ChemMedChem | Year: 2013

Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di- and tri-n-butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT-29 and MCF-7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di-n-butyltin(IV) complex as an example. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kohl S.,Harvard University | Kohl S.,Cologne Childrens Hospital | Chen J.,Harvard University | Vivante A.,Harvard University | And 17 more authors.
Nephrology Dialysis Transplantation | Year: 2016

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. MethodsGiven the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. ResultsWe sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. ConclusionsOur results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans. © 2016 The Author 2016.


Geldmacher Y.,Ruhr University Bochum | Splith K.,University of Cologne | Kitanovic I.,University of Heidelberg | Alborzinia H.,University of Heidelberg | And 9 more authors.
Journal of Biological Inorganic Chemistry | Year: 2012

Half-sandwich organorhodium(III) complexes and their trichloridorhodium(III) counterparts are potent anticancer agents that enhance the formation of reactive oxygen species and invoke a strong induction of apoptosis in leukemia cells. The antiproliferative activity towards human MCF-7 and HT-29 adenocarcinoma cells of novel nonintercalating complexes containing the 5-substituted phenanthroline ligands 5,6-dimethylphenanthroline, 5-chlorophenanthroline, and 5-nitrophenanthroline (phen*) increases dramatically in the order [(g5-C5Me5)IrCl (phen*)](CF3SO3)\[(g5-C5Me5) RhCl(phen*)](CF3SO3)


Bieda R.,Ruhr University Bochum | Dobroschke M.,Cologne Childrens Hospital | Triller A.,Ruhr University Bochum | Ott I.,TU Braunschweig | And 4 more authors.
ChemMedChem | Year: 2010

Half-sandwich rhodium(III) polypyridyl (pp) complexes with the metal atom capped by the facial crown thiaether 1,4,7-trithia-cyclononane [9]aneS 3 represent a promising class of apoptosis-inducing potent cytostatic agents. The necrotic damage caused by the complexes is negligible. In vitro cytotoxicity assays with the human cancer cell lines MCF-7 and HT-29 and immortalized HEK-293 cells indicate that the dicationic κ2N- (imino) complexes [([9]aneS3)RhCl(pp)]2+ are much more active than monocationic complexes [([9]aneS3)RhCl 2(L)]+ (L=imidazole, CH3CN). Whereas the κ2N(amino) complex [([9]aneS3)-RhCl(piperazine)] 2+ is inactive, replacing piperazine with the structurally analogous κ2S (thiaether) ligand 1,4-dithiane restores cytotoxicity as evidenced by IC50 values in the range 8.1-11.6 μm. Spectroscopic (CD, UV/Vis, NOESY) and viscosity measurements indicate that the active dppz complex 8 (IC50 values: 4.7-8.9 μm) exhibits strong intercalative binding towards DNA whereas the even more potent bipyrimidine complex 9 (IC 50 values: 0.6-1.9 μm) causes no alteration of the duplex B conformation. Weaker intercalative binding is observed for the dpq complex 7. A comparative annexin V-propidium iodide binding assay with lymphoma (BJAB) cells and healthy leukocytes demonstrates that the cytotoxic activity of complex 8 and particularly complex 9 is highly selective towards the malignant cells. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Geldmacher Y.,Ruhr University Bochum | Rubbiani R.,TU Braunschweig | Wefelmeier P.,Cologne Childrens Hospital | Prokop A.,Cologne Childrens Hospital | And 2 more authors.
Journal of Organometallic Chemistry | Year: 2011

Half-sandwich organorhodium(III) complexes of the type [(η 5- C 5Me 5)RhCl(pp)] (CF 3SO 3) containing polypyridyl ligands (pp) represent a promising class of cytostatic agents. Replacement of the polypyridyl ligands of complexes 1 (pp = phen) and 6 (pp = dppz) by methyl-substituted derivatives in 2-5 (pp = 4-Mephen, 5-Mephen, 4,7-Me 2phen, 5,6-Me 2phen) and 7 (pp = Me 2dppz) leads to a significant improvement in their antiproliferative activity towards human MCF-7 and HT-29 cancer cells. For instance, the IC 50 value towards HT-29 cells decreases from 4.3 ± 0.2 μM for 6 to 0.98 ± 0.49 μM for complex 7. In contrast, no activity (IC 50 > 100 μM) was observed for the HOOC and n-BuNHCO substituted dppz complexes 8 and 9. UV/vis, CD and NMR spectra for mixtures of complexes 7-9 with CT DNA were in accordance with intercalation of the substituted dppz ligands between the base pairs of the double helix and direct evidence for this binding mode was also provided by a 2D NOESY study for complex 7 with the hexanucleotide d(5′-CGTCGG-3′). Each of the methyl-substituted phen complexes 2-5 is significantly more active towards immortalized HEK-293 cells (IC 50 values 0.40 ± 0.02 to 0.94 ± 0.02 μM) than towards the cancer cells. Flow cytometric measurements of DNA fragmentation in BJAB cells following an incubation period of 72 h with 1, 5 and 6 indicate that the complexes induce specific apoptotic cell death in the non-adherent lymphoma cells. © 2011 Elsevier B.V. All rights reserved.


Navakoski De Oliveira K.,TU Braunschweig | Andermark V.,TU Braunschweig | Onambele L.A.,Cologne Childrens Hospital | Dahl G.,Cologne Childrens Hospital | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Di-n-butyltin(IV) carboxylate and tri-n-butyltin(IV) carboxylate derivatives have demonstrated strong cytotoxic effects in different types of tumor cells. Complexes with carboxylate ligands that contain maleimide and naphthalimide derived partial structures were synthesized, characterized and investigated for inhibition of the tumor-relevant enzyme thioredoxin reductase and antiproliferative effects in cancer cells. The complexes were moderate inhibitors of thioredoxin reductase with activities in the micromolar range and triggered strong cytotoxic effects in MCF-7 breast cancer and HT-29 colon carcinoma cells. Interestingly, selected complexes were highly active in vincristine and daunorubicin resistant Nalm-6 cells. © 2014 Elsevier Masson SAS. All rights reserved.

Loading Cologne Childrens Hospital collaborators
Loading Cologne Childrens Hospital collaborators