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Matthias Tacke - One of the best experts on this subject based on the ideXlab platform.
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The Activity of Titanocene T Against Xenografted Caki-1 Tumors
Letters in Drug Design & Discovery, 2013Co-Authors: Wolfgang Walther, Anthony Deally, Megan Hogan, Iduna Fichtner, Matthias TackeAbstract:The indole-substituted Titanocene dichloride derivative Titanocene T, which is completely water-soluble and shows micromolar activity against the human renal cancer cells Caki-1, was tested in vivo an against xenografted human renal cell tumors in mice. Titanocene T was then given at 25 and 50 mg/kg, seven times every four days during three weeks to two groups (n=6) of Caki-1 tumor-bearing female NMRI: nu/nu mice, while the control group was treated with solvent only. At both doses Titanocene T induced a moderate to good tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 51% and 32% and showed neither mortality nor toxicity. Immunohistochemical analysis revealed that the expression of the proliferation marker Ki-67 was reduced in the high-dosage group. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 27% and 29% due to Titanocene T treatment.
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Synthesis and Cytotoxicity Studies of Silyl-Substituted Titanocene Dichloride Derivatives
Organometallics, 2012Co-Authors: Anthony Deally, Helge Müller-bunz, Frauke Hackenberg, Grainne Lally, Matthias TackeAbstract:Six new Titanocene compounds have been isolated and characterized. These compounds were synthesized from their silyl-substituted fulvene or cyclopentadiene precursors using Super Hydride (LiBEt3H) or n-BuLi, followed by transmetalation with titanium tetrachloride, to yield the corresponding Titanocene dichloride derivatives. These complexes are bis-[((phenyl)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3a), bis-[((4-methoxyphenyl)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3b), bis-[((4-N,N-dimethylmethanamine)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3c), bis-[((4-N,N-diethylmethanamine)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3d), bis-[((1-methyl-5-trimethylsilyl)indol-3-yl)methylcyclopentadienyl] titanium(IV) dichloride (4e), and bis-[((1-methyl-3-diethylaminomethyl-5-trimethylsilyl)indol-2-yl)methylcyclopentadienyl] titanium(IV) dichloride (4f). The two Titanocenes 3a and 3b were crystallized and characterized by X-ray crystallography, while ...
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Towards peptide-substituted Titanocene anticancer drugs
Polyhedron, 2011Co-Authors: Johannes Zagermann, Helge Müller-bunz, Denise Wallis, Anthony Deally, Nils Metzler-nolte, Matthias TackeAbstract:Abstract An alkyne-substituted fulvene was transformed via hydridolithiation followed by transmetallation with titanium tetrachloride into bis-[p-(prop-2-ynyloxy)-benzyl-cyclopentadienyl] titanium(IV) dichloride. Single crystals of this Titanocene derivative could be obtained and the structure determined by X-ray diffraction. It showed that this compound crystallises in the space group C2/c with four molecules in the monoclinic cell. The alkyne-substituted Titanocene dichloride derivative was then subject to a copper-catalysed azide–alkyne cycloaddition with its azide-functionalised methylester-protected phenylalanine reaction partner in order to form a linking triazole. This reaction was performed under anhydrous conditions employing a dichloromethane/acetonitrile solvent mixture with copper(I) iodide and 2,6-lutidine as the catalyst system. Under these conditions the adduct between the protein mimic and the Titanocene was formed without hydrolysing the titanium dichloride moiety.
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The Antiangiogenic and Antitumoral Activity of Titanocene Y* In Vivo
Letters in Drug Design & Discovery, 2011Co-Authors: Iduna Fichtner, James Claffey, Brendan Gleeson, Anthony Deally, Holger Weber, Diana Behrens, Siddappa A. Patil, Matthias TackeAbstract: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 {Mu}M. 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.
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Anticancer activity and mode of action of Titanocene C
Investigational New Drugs, 2010Co-Authors: Ulrike Olszewski, Matthias Tacke, James Claffey, Megan Hogan, Robert Zeillinger, Patrick J. Bednarski, Gerhard HamiltonAbstract:Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, Titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC50 value of 48.3 ± 32.5 µM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for Titanocene C and absent for Titanocene Y in variant HL-60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by Titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIα, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to Titanocene C. Approximately 50% of those genes downregulated by Titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of Titanocene C and metallothioneins as putative main effectors of drug resistance.
Nigel J. Sweeney - One of the best experts on this subject based on the ideXlab platform.
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anti tumor activity of Titanocene y in xenografted caki 1 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Iduna Fichtner, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, Matthias TackeAbstract:The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10(-6) mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.
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Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Catherine M. Dowling, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, James Claffey, Iduna Fichtner, Sandra Cuffe, R. William G. Watson, Matthias TackeAbstract:Chemotherapeutic options for androgen-independent prostate cancer are extremely limited with minimum survival advantage. The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl) cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against the human prostate cancer androgen-independent cell, PC-3, which demonstrated an IC50 value of 56 x 10(-6) mol/L compared to 5.6 x 10(-6) mol/L for cisplatin. Then Titanocene Y was given at the maximum tolerable dose of 40 mg/kg/d on five consecutive days to one cohort of eight PC3 tumor-bearing male NMRI: nu/nu mice, while a second cohort was treated similarly with 3 mg/kg/d of cisplatin. Both of these mouse cohorts showed a statistically significant tumor growth reduction with respect to the third solvent-treated control group, which led to T/C values of 42% for cisplatin and 52% for Titanocene Y at the end of the experiment. This encouraging activity of Titanocene Y against prostate tumors in vivo, which is almost comparable with respect to cisplatin hopefully leads to further development of Titanocene Y in the future.
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Antiproliferative activity of Titanocene Y against tumor colony-forming units.
Anti-Cancer Drugs, 2007Co-Authors: Olaf Oberschmidt, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, Axel R. Hanauske, Matthias TackeAbstract:Bis-[(p-methoxybenzyl)cyclopentadienyl] titanium dichloride, better known as Titanocene Y, is a newly synthesized titanium-based anticancer drug. We studied the antitumor activity of Titanocene Y with concentrations of 2.1, 21 and 210 μmol/l against a range of freshly explanted human tumors, using an in-vitro soft agar cloning system. The sensitivity against Titanocene Y was highly remarkable in the case of renal cell, ovarian, nonsmall cell lung and colon cancer. In particular the surprisingly good response of nonsmall cell lung cancer and colon cancer against Titanocene Y at its lowest concentration of 2.1 μmol/l was well comparable or better with respect to cisplatin, given at a concentration of 1.0 μmol/l. Further clinical development of Titanocene Y appears to be warranted because of the broad cytotoxic activity shown and the specific activity of Titanocene Y against renal cell cancer.
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The synthesis and cytotoxic evaluation of a series of benzodioxole substituted Titanocenes
Applied Organometallic Chemistry, 2007Co-Authors: Nigel J. Sweeney, Katja Strohfeldt, Helge Müller-bunz, Clara Pampillón, James Claffey, Matthias TackeAbstract:Using 6-benzo[1,3]dioxolefulvene (1a), a series of benzodioxole substituted Titanocenes was synthesized. The benzyl-substituted Titanocene bis[(benzo[1,3]dioxole)-5-methylcyclopentadienyl] titanium (IV) dichloride (2a) was synthesized from the reaction of Super Hydride with 1a. An X-ray determined crystal structure was obtained for 2a. The ansa-Titanocene (1,2-di(cyclopentadienyl)1,2-di-(benzo[1,3]dioxole)-ethanediyl) titanium(IV) dichloride (2b) was synthesized by reductive dimerisation of la with titanium dichloride. The diarylmethyl substituted Titanocene bis(di(benzo[1,3]dioxole)-S-methylcyclopentadienyl) titanium(IV) dichloride (20 was synthesized by reacting la with the para-lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When Titanocenes 2a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 2.8 X 10(-4), 1.6 x 10(-4) and 7.6 x 10(-5) m, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared with unsubstituted Titanocene dichloride, but are not as impressive as values obtained for Titanocenes previously synthesized using the above methods. Copyright (c) 2006 John Wiley & Sons, Ltd.
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Glycol Methyl Ether and Glycol Amine Substituted Titanocenes as Antitumor Agents
European Journal of Inorganic Chemistry, 2006Co-Authors: Katja Strohfeldt, Helge Müller-bunz, Clara Pampillón, Nigel J. Sweeney, Matthias TackeAbstract:6-[4-(2-Methoxyethoxy)phenyl]fulvene (3a) and 6-{4-[2-(dimethylamino)ethoxy]phenyl}fulvene (3b) were prepared as the starting materials for the synthesis of three different classes of Titanocenes, which are ansa-Titanocenes, diarylmethyl-substituted Titanocenes and benzyl-substituted Titanocenes. Because the synthetic possibilities seem to be limited, only ansa-Titanocene {1,2-bis(cyclopentadienyl)-1,2-bis[4-(2-methoxyethoxy)phenyl]ethanediyl}titanium dichloride (4a) and benzyl-substituted Titanocene bis-{[4-(2-methoxyethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (6a) were obtained and characterised. The change in the substitution pattern of the phenyl moiety from an oxygen atom to a nitrogen atom had such a big influence on the reaction that not one compound of the three Titanocene classes could be synthesised, and it was also not possible to obtain diarylmethyl-substituted Titanocenes with the use of either of the fulvenes. When benzyl-substituted Titanocene 6a was tested against pig kidney cells (LLC-PK), an antiproliferative effect that results in an IC50 value of 43 μM, was observed. This IC50 value is in the lower range of the cytotoxicities evaluated for Titanocenes up to now. ansa-Titanocene 4a surprisingly showed, when tested on the same cell line, a proliferative effect together with a fast rate of hydrolysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Andreas Gansäuer - One of the best experts on this subject based on the ideXlab platform.
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tuning the redox properties of the Titanocene iii iv couple for atom economical catalysis in single electron steps
Dalton Transactions, 2016Co-Authors: Andreas Gansäuer, Sven Hildebrandt, Elisabeth Vogelsang, Robert A FlowersAbstract:Radical-based transformations are an attractive target for the development of catalytic processes due to ease of radical generation, high functional group tolerance and selectivity of bond-forming reactions. In spite of these appealing features, the potential of radicals as key intermediates in catalysis remains largely untapped. Herein we present recent work that exploits the innate ability of Titanocene-based catalysts to undergo both oxidative addition and reductive elimination in single electron steps. We further demonstrate that tuning the redox properties of the Titanocene-based catalyst can be used to develop efficient catalytic free radical processes including tetrahydrofuran synthesis, and radical arylation.
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Triazol-substituted Titanocenes by strain-driven 1,3-dipolar cycloadditions
Beilstein Journal of Organic Chemistry, 2014Co-Authors: Andreas Gansäuer, Andreas Okkel, Lukas Schwach, Laura Wagner, Anja Selig, Aram ProkopAbstract:An operationally simple, convenient, and mild strategy for the synthesis of triazole-substituted Titanocenes via strain-driven 1,3-dipolar cycloadditions between azide-functionalized Titanocenes and cyclooctyne has been developed. It features the first synthesis of Titanocenes containing azide groups. These compounds constitute ‘second-generation’ functionalized Titanocene building blocks for further synthetic elaboration. Our synthesis is modular and large numbers of the complexes can in principle be prepared in short periods of time. Some of the triazole-substituted Titanocenes display high cyctotoxic activity against BJAB cells. Comparison of the most active complexes allows the identification of structural features essential for biological activity.
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highly regioselective and chemoselective Titanocene mediated barbier type allylation reactions
Chemical Communications, 2014Co-Authors: Sara P Morcillo, Christian Kube, Angela Martinezperagon, Verena Jakoby, Antonio J Mota, Jose Justicia, Juan M Cuerva, Andreas GansäuerAbstract:Titanocene carboxylate 1 is an excellent chemoselective reagent for unprecedented α-regioselective Barbier-type reactions. It constitutes the first Titanocene(III) able to tolerate epoxides and readily reduced carbonyl compounds, such as aromatic and α,β-unsaturated aldehydes.
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substituent effects and supramolecular interactions of Titanocene iii chloride implications for catalysis in single electron steps
Journal of the American Chemical Society, 2014Co-Authors: Andreas Gansäuer, Christian Kube, Kim Daasbjerg, Rebecca Sure, Stefan Grimme, Godfred D Fianu, Dhandapani V Sadasivam, Robert A FlowersAbstract:The electrochemical properties of Titanocene(III) complexes and their stability in THF in the presence and absence of chloride additives were studied by cyclic voltammetry (CV) and computational methods. The anodic peak potentials of the Titanocenes can be decreased by as much as 0.47 V through the addition of an electron-withdrawing substituent (CO2Me or CN) to the cyclopentadienyl ring when compared with Cp2TiCl. For the first time, it is demonstrated that under the conditions of catalytic applications low-valent Titanocenes can decompose by loss of the substituted ligand. The recently discovered effect of stabilizing Titanocene(III) catalysts by chloride additives was analyzed by CV, kinetic, and computational studies. An unprecedented supramolecular interaction between [(C5H4R)2TiCl2]− and hydrochloride cations through reversible hydrogen bonding is proposed as a mechanism for the action of the additives. This study provides the critical information required for the rational design of Titanocene-catal...
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Radical-Based Epoxide Opening by Titanocenes
Inorganic Chemistry, 2013Co-Authors: Asli Cangönül, Andreas Gansäuer, Maike Behlendorf, Maurice Van GastelAbstract:The binding of 2,2-diphenyloxirane to Cp2TiCl is studied on the electronic level by magnetic resonance spectroscopy and quantum chemical calculations. The complexation of 2,2-diphenyloxirane is accompanied by dissociation of the chloride ligand, and thus, the epoxide binds to the cationic Titanocene(III) complex. The Titanocene(III)–epoxide species persists only for short periods of time (
Clara Pampillón - One of the best experts on this subject based on the ideXlab platform.
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anti tumor activity of Titanocene y in xenografted caki 1 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Iduna Fichtner, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, Matthias TackeAbstract:The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10(-6) mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.
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Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Catherine M. Dowling, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, James Claffey, Iduna Fichtner, Sandra Cuffe, R. William G. Watson, Matthias TackeAbstract:Chemotherapeutic options for androgen-independent prostate cancer are extremely limited with minimum survival advantage. The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl) cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against the human prostate cancer androgen-independent cell, PC-3, which demonstrated an IC50 value of 56 x 10(-6) mol/L compared to 5.6 x 10(-6) mol/L for cisplatin. Then Titanocene Y was given at the maximum tolerable dose of 40 mg/kg/d on five consecutive days to one cohort of eight PC3 tumor-bearing male NMRI: nu/nu mice, while a second cohort was treated similarly with 3 mg/kg/d of cisplatin. Both of these mouse cohorts showed a statistically significant tumor growth reduction with respect to the third solvent-treated control group, which led to T/C values of 42% for cisplatin and 52% for Titanocene Y at the end of the experiment. This encouraging activity of Titanocene Y against prostate tumors in vivo, which is almost comparable with respect to cisplatin hopefully leads to further development of Titanocene Y in the future.
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Synthesis and cytotoxicity studies of methoxy benzyl substituted Titanocenes
Journal of Organometallic Chemistry, 2008Co-Authors: James Claffey, Helge Müller-bunz, Clara Pampillón, Megan Hogan, Matthias TackeAbstract:Abstract From the reaction of 6(2-methoxy-phenyl)fulvene ( 1a ), 6(3-methoxy-phenyl)fulvene ( 1b ), 6(3,4-dimethoxy-phenyl)fulvene ( 1c ) and 6(3,4,5-trimethoxy-phenyl)fulvene ( 1d ) with LiBEt 3 H, lithiated cyclopentadienide intermediates 2a – d were synthesised. These intermediates were then transmetallated to titanium with TiCl 4 to give benzyl substituted Titanocenes bis-[(2-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3a ), bis-[(3-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3b ), bis-[(3,4-dimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3c ) and bis-[(3,4,5-trimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3d ). The three Titanocenes 3a – c were characterised by single crystal X-ray diffraction, while the structure of the fourth Titanocene 3d was elucidated through a DFT calculation. All four Titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC 50 values. Titanocenes 3a – d were found to have IC 50 values of 97, 159, 88 and 253 μM, respectively. All four Titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted Titanocene dichloride.
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Synthesis and Cytotoxicity Studies of Titanocene C Analogues
Metal-based Drugs, 2008Co-Authors: Megan Hogan, Clara Pampillón, Thomas Hickey, James Claffey, Eoin Fitzpatrick, Matthias TackeAbstract:From the carbolithiation of 6-N,N-dimethylamino fulvene (3) and 2,4[bis(N,N-dimethylamino)methyl]-N-methylpyrrolyl lithium (2a), N-(N′,N′-dimethylaminomethyl)benzimidazolyl lithium (2b)' or p-(N,N-dimethylamino)methylphenyl lithium (2c), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4' resulting in N,N-dimethylamino-functionalised Titanocenes 5a–c. When these Titanocenes were tested against a pig kidney epithelial cell line (LLC-PK), the IC50 values obtained were of 23, and 52 μM for Titanocenes 5a and 5b, respectively. The most cytotoxic Titanocene in this paper, 5c with an IC50 value of 13 μM, was found to be approximately two times less cytotoxic than its analogue Titanocene C (IC50=5.5 μM) and almost four times less cytotoxic than cisplatin, which showed an IC50 value of 3.3 μM when tested on the LLC-PK cell line.
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Dimethylamino-functionalised and N-heteroaryl-substituted Titanocene anticancer drugs: synthesis and cytotoxicity studies
Investigational New Drugs, 2007Co-Authors: Thomas Hickey, Clara Pampillón, James Claffey, Eoin Fitzpatrick, Megan Hogan, Matthias TackeAbstract:From the carbolithiation of 6- N,N -dimethylamino fulvene (3a) and different lithiated N -heterocyclic compounds ( N,N- dimethylaminomethylpyrrole, 1-methylimidazole and 2,4-[bis( N′,N′ -dimethylaminomethyl)]- N -methyl pyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl_4 resulting in dimethylamino-functionalised Titanocenes 5a–c. When these Titanocenes were tested against LLC-PK cells, the IC_50 values obtained were of 13, and 63 μM for Titanocenes 5b and 5c, respectively. The most cytotoxic Titanocene in this paper (5a) with an IC_50 value of 6.8 μM is found to be almost as cytotoxic as cis -platin, which showed an IC_50 value of 3.3 μM, when tested on the epithelial pig kidney LLC-PK cell line, and Titanocene 5c is approximately 400 times better than Titanocene dichloride itself.
Katja Strohfeldt - One of the best experts on this subject based on the ideXlab platform.
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Titanocene anticancer complexes and their binding mode of action to human serum albumin: A computational study
Metallomics, 2011Co-Authors: Susan W. Sarsam, Katja Strohfeldt, David R. Nutt, Kimberly A. WatsonAbstract:Due to the pivotal role played by human serum albumin (HSA) in the transport and cytotoxicity of Titanocene complexes, a docking study has been performed on a selected set of Titanocene complexes to aid in the current understanding of the potential mode of action of these Titanocenes upon binding HSA. Analysis of the docking results has revealed potential binding at the known drug binding sites in HSA and has provided some explanation for the specificity and subsequent cytotoxicity of these Titanocenes. Additionally, a new alternative binding site for these Titanocenes has been postulated.
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anti tumor activity of Titanocene y in xenografted caki 1 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Iduna Fichtner, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, Matthias TackeAbstract:The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10(-6) mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.
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Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice
Letters in Drug Design & Discovery, 2008Co-Authors: Catherine M. Dowling, Katja Strohfeldt, Clara Pampillón, Nigel J. Sweeney, James Claffey, Iduna Fichtner, Sandra Cuffe, R. William G. Watson, Matthias TackeAbstract:Chemotherapeutic options for androgen-independent prostate cancer are extremely limited with minimum survival advantage. The benzyl-substituted unbridged Titanocene bis-[(p-methoxybenzyl) cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against the human prostate cancer androgen-independent cell, PC-3, which demonstrated an IC50 value of 56 x 10(-6) mol/L compared to 5.6 x 10(-6) mol/L for cisplatin. Then Titanocene Y was given at the maximum tolerable dose of 40 mg/kg/d on five consecutive days to one cohort of eight PC3 tumor-bearing male NMRI: nu/nu mice, while a second cohort was treated similarly with 3 mg/kg/d of cisplatin. Both of these mouse cohorts showed a statistically significant tumor growth reduction with respect to the third solvent-treated control group, which led to T/C values of 42% for cisplatin and 52% for Titanocene Y at the end of the experiment. This encouraging activity of Titanocene Y against prostate tumors in vivo, which is almost comparable with respect to cisplatin hopefully leads to further development of Titanocene Y in the future.
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Proliferative and antiproliferative effects in substituted Titanocene anticancer drugs
Transition Metal Chemistry, 2007Co-Authors: Katja Strohfeldt, Helge Müller-bunz, Clara Pampillón, Matthias TackeAbstract:Substituted Titanocenes like ansa-Titanocenes, diarylmethyl-substituted and benzyl-substituted Titanocenes, are known for their cytotoxic potential and they can be synthesised using 6-arylfulvenes. Nevertheless, in the case of using 6-(4-morpholin-4yl-phenyl) fulvene (5a) or 6-{[bis-(2-methoxyethyl)amino]phenyl} fulvene (5b) the synthetic possibilities seem to be limited, but the morpholino and the bis-(2-methoxyethyl)amino substituent are in terms of an improved water solubility and drug availability in the cell very interesting groups. The corresponding benzaldehydes, which are the starting material for the synthesis of these fulvenes, were not commercially available and therefore, a modified synthetic approach had to be introduced. Nevertheless, the reactivity of the obtained fulvenes was unexpected and only the ansa-Titanocene bis-[{[bis-(2-methoxyethyl)amino]phenyl}cyclopentadienyl] titanium(IV) dichloride (6b) and the benzyl-substituted Titanocene [1,2-di(cyclopentadienyl)-1,2-di(4-morpholin-4yl-phenyl)-ethanediyl] titanium dichloride (8a) could be obtained and characterised.
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Synthesis and cytotoxicity studies of new dimethylamino-functionalised and indolyl-substituted Titanocene anti-cancer drugs
Transition Metal Chemistry, 2007Co-Authors: Clara Pampillón, Katja Strohfeldt, James Claffey, Megan Hogan, Matthias TackeAbstract:From the carbolithiation of 6- N , N -dimethylamino fulvene (3a) and different ortho-lithiated indole derivatives (5-methoxy- N -methylindole, N -methylindole and N , N -dimethylaminomethylindole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl_4 resulting in dimethylamino-functionalised Titanocenes (5a–c) . When these Titanocenes were tested against LLC-PK cells, the IC_50 values obtained were of 37 and 71 μ M for Titanocenes 5a and 5b respectively. The most cytotoxic Titanocene in this paper, 5c showed an IC_50 value of 8.4 μ M is found to be almost as cytotoxic as cis -platin, which showed an IC_50 value of 3.3 μ M , when tested on the LLC-PK cell line, and Titanocene 5c is approximately 250 times better than Titanocene dichloride itself. Graphical Abstract Bis-( N , N -dimethylamino-2-( N -methylindolyl)methylcyclopentadienyl) titanium (IV) dichloride was synthesised starting from 2-( N -methylindolyl) lithium and 6- N , N -dimethylamino fulvene. Herein, we present the synthesis and DFT structure of the Titanocene and two further derivatives followed by MTT-based cytotoxicity tests on LLC-PK cells.
