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Fichtner I.,Max Delbrück Center for Molecular Medicine | Behrens D.,Experimental Pharmacology and Oncology EPO GmbH | Claffey J.,University College Dublin | Deally A.,University College Dublin | And 4 more authors.
Letters in Drug Design and Discovery | Year: 2011

The 4-diethylaminomethylbenzyl-substituted titanocene dichloride (Titanocene Y*), which is completely water-soluble and showed nanomolar activity against the human renal cancer cells CAKI-1, was tested in vitro in an antiangiogenesis assay against human umbilical vein endothelial cells, HUVEC, delivering an IC50 value of 23 +/- 17 μM. Titanocene Y* was then given at 25, 50 and 75 mg/kg/d, on five consecutive days per week for up to three weeks to one cohort of six CAKI-1 tumor-bearing female NMRI:nu/nu mice, while a further cohort was treated with solvent only. At the two higher dosages Titanocene Y* showed high toxicity leading to mortality, while the titanocene-treated mouse cohort treated with the lowest dosage showed a moderate but statistically significant tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 76% at the end of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced by 21%. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 23% due to Titanocene Y* treatment. The substance caused dose-dependent body weight loss but did not reduce the number of white blood cells at doses of 25 and 50 mg/kg/d. © 2011 Bentham Science Publishers Ltd.


Fichtner I.,Max Delbrück Center for Molecular Medicine | Claffey J.,Conway Institute of Biomolecular and Biomedical Research | Deally A.,Conway Institute of Biomolecular and Biomedical Research | Gleeson B.,Conway Institute of Biomolecular and Biomedical Research | And 5 more authors.
Journal of Organometallic Chemistry | Year: 2010

The para-methoxybenzyl-substituted vanadocene dichloride (Vanadocene Y) (1) and its diselenocyanate (Selenocyanato-Vanadocene Y) (2) were tested in vitro in an anti-angiogenesis assay against human umbilical vein endothelial cells (HUVEC) delivering IC50 values of 0.92 ± 0.03 μM (1) and 37 ± 11 μM (2). In a cytotoxicity assay against the human renal cancer cells, CAKI-1, the compounds demonstrated IC50 values of 0.55 ± 0.09 μM (1) and 0.25 ± 0.03 μM (2). Then both compounds were given at their maximum tolerable dose, MTD, of 20 mg/kg/d (1) or 40 mg/kg/d (2) on four consecutive days or at 50% of the MTD on five consecutive days per week for three weeks to overall four cohorts of eight CAKI-1 tumor-bearing female NMRI:nu/nu mice each, while a further cohort was treated with solvent only. Both MTD-treated mouse cohorts showed a statistically significant tumor growth reduction with respect to the solvent-treated control group with an optimal T/C value of 47% on day 39 of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced due to long-term treatment with 2. © 2010 Elsevier B.V. All rights reserved.


Mahmoud K.A.,Martin Luther University of Halle Wittenberg | Wersig T.,Martin Luther University of Halle Wittenberg | Slynko I.,Martin Luther University of Halle Wittenberg | Totzke F.,ProQinase GmbH Freiburg | And 5 more authors.
MedChemComm | Year: 2014

Novel 4-anilino pyrido[2,3-b]indoles have been discovered as inhibitors of the breast cancer relevant protein kinase Brk. Within this first series favourable aniline substituents have been characterized. Combinations with substituents of the molecular scaffold have been further investigated and led to additional nanomolar Brk inhibitors. Due to the reported role of Brk in breast cancer progression via HER2 activation we determined the inhibition profile of our novel Brk inhibitors to additionally inhibit HER2. These studies characterized the first dually acting Brk and HER2 inhibitor and the first exclusive HER2 inhibitors. This journal is © the Partner Organisations 2014.


Tell V.,Martin Luther University of Halle Wittenberg | Mahmoud K.A.,Martin Luther University of Halle Wittenberg | Wichapong K.,Martin Luther University of Halle Wittenberg | Schachtele C.,ProQinase GmbH Freiburg | And 3 more authors.
MedChemComm | Year: 2012

A novel series of derivatized 1-aza-9-oxafluorenes has been synthesized. Structure-directed substituents have been introduced and their effect on the inhibition of Alzheimer's disease-relevant kinases has been determined in in vitro assays. Novel structure-activity relationships were found depending on the varying substituents. Nanomolar inhibitors have been identified as promising candidates for the treatment of Alzheimer's disease. © The Royal Society of Chemistry.


Mahmoud K.A.,Martin Luther University of Halle Wittenberg | Krug M.,Martin Luther University of Halle Wittenberg | Wersig T.,Martin Luther University of Halle Wittenberg | Slynko I.,Martin Luther University of Halle Wittenberg | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Dysregulation of cell signalling processes caused by an enhanced activity of protein kinases mainly contributes to cancer progression. Protein kinase inhibitors have been established as promising drugs that inhibit such overactive protein kinases in cancer cells. The formation of metastases, which makes a therapy difficult, remains a great challenge for cancer treatment. Recently, breast tumor kinase (Brk) was discovered as novel and interesting target for a cancer therapy because Brk participates in both cell dysregulation and metastasis. We discovered 4-anilino substituted α-carboline compounds as a novel class of highly active Brk inhibitors. In the current work, structure-activity relationships are discussed including docking results obtained for 4-anilino α-carbolines. A first profiling of selective kinase inhibition and a proof of concept for the antiproliferative effects is demonstrated. These results qualify the compounds as a promising class of novel antitumor agents. © 2014 Elsevier Ltd. All rights reserved.

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