Matthias Tacke

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Organization: University College Dublin , Ireland

Department: Chemistry Department

Title: (PhD)

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Inorganic Chemistry

Chemicals
References

Synthesis and cytotoxicity studies of novel NHC–Gold(I) pseudohalides and thiolates

Co-reporter:Oyinlola Dada, Danielle Curran, Cillian O'Beirne, Helge Müller-Bunz, Xiangming Zhu, Matthias Tacke

Journal of Organometallic Chemistry 2017 Volume 840(Volume 840) pp:

Publication Date(Web):1 July 2017

DOI:10.1016/j.jorganchem.2017.03.050

•Two series of NHC-Au(I)X complexes are reported.•All compounds are fully characterized chemically.•All compounds are tested on the NCI 60 cancer cell panel.•Two compounds show promising anticancer activity.The synthesis and biological evaluation of three gold pseudohalides and three gold thiolates, stabilised by the NHC ligand 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene (NHC*), in order to form stable gold(I) complexes is reported. Two separate procedures have been developed for the synthesis; the one for the pseudohalide complexes employs the use of a biphasic medium while the one for the thiolate complexes requires higher temperature for their formation. The gold complexes have been prepared in varying yields (44–81%) from the corresponding NHC*-Au-Cl precursor. One thiolate and two pseudohalide gold complexes were characterized by single crystal X-ray diffraction and showed the expected monomeric nature of all derivatives. All six complexes were submitted to the NCI 60 cancer cell panel for cytotoxicity tests; most of the complexes showed activity in the medium to low micromolar region, while the NHC*-Au-SCN derivative was superior exhibiting nanomolar anticancer activity.Six NHC-Au(I) pseudohalides and thiolates were synthesized and tested as anticancer drug candidates.Download high-res image (191KB)Download full-size image

Benzyl-substituted carbene–metal complexes: Potential for novel antibiotics and anticancer drugs?

Co-reporter:Matthias Tacke

Journal of Organometallic Chemistry 2015 Volume 782() pp:17-21

Publication Date(Web):15 April 2015

DOI:10.1016/j.jorganchem.2014.09.036

•Ag, Cu, Au and Ru complexes of benzyl-substituted NHC ligands are reviewed.•The NHC–Cu–Br derivative WBC4 is an effective anticancer drug candidate.•The NHC–Ag–OAc derivative SBC3 is a potential antibiotic drug candidate.Benzyl-substituted metallocarbene compounds synthesized by our group and others during the past 5 years give a new perspective on their activity as antibiotic and antitumoral drugs. N-Heterocyclic carbene (NHC) containing Au and Ru compounds have shown promising anticancer activity in vitro and the Cu derivative WBC4 showed strong cytotoxic efficacy in vivo xenograft studies against difficult to treat renal cell cancer. While the carbene–silver acetate derivative SBC1 failed in vivo as an anticancer drug the antibacterial derivative SBC3 convinced in vivo and this compound may lead the way towards novel injectable emergency antibiotics against resistant bacteria and fungi.Covalently bonded NHC–metal complexes derived from the coinage metals and ruthenium have the potential to become either resistance-breaking antibiotics or anticancer drugs against difficult to treat solid human tumors.

Synthesis and cytotoxicity studies of p-benzyl substituted NHC–copper(I) bromide derivatives

Co-reporter:Wojciech Streciwilk, Frauke Hackenberg, Helge Müller-Bunz, Matthias Tacke

Polyhedron 2014 80() pp: 3-9

Publication Date(Web):

DOI:10.1016/j.poly.2013.11.039

Synthesis, cytotoxic and antibacterial studies of p-benzyl-substituted NHC–silver(I) acetate compounds derived from 4,5-di-p-diisopropylphenyl- or 4,5-di-p-chlorophenyl-1H-imidazole

Co-reporter:Wojciech Streciwilk, Jennifer Cassidy, Frauke Hackenberg, Helge Müller-Bunz, Francesca Paradisi, Matthias Tacke

Journal of Organometallic Chemistry 2014 749() pp: 88-99

Publication Date(Web):

DOI:10.1016/j.jorganchem.2013.09.033

Synthesis and biological evaluation of N-heterocyclic carbene–silver(I) acetate complexes derived from 4,5-ditolyl-imidazole

Co-reporter:Frauke Hackenberg, Grainne Lally, Helge Müller-Bunz, Francesca Paradisi, Daniela Quaglia, Wojciech Streciwilk, Matthias Tacke

Inorganica Chimica Acta 2013 Volume 395() pp:135-144

Publication Date(Web):30 January 2013

DOI:10.1016/j.ica.2012.10.029

From the reaction of 1,2-bis-(4-methylphenyl)ethane-1,2-dione with formamide, symmetrically substituted 4,5-bis-(4-methylphenyl)-1H-imidazole (1) was synthesised and further reacted with p-benzyl substituted halides to give the symmetrically substituted N-heterocyclic carbene (NHC) precursors 1a–e.The NHC precursors were then reacted with silver(I) acetate to yield NHC–silver(I) acetate complexes 1,3-bis-(benzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2a), 1,3-bis-(4-methylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2b), 1,3-bis-(4-methoxylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2c), 1,3-bis-(4-methoxycarbonylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2d) and 1,3-bis-(4-cyanobenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2e).Two NHC–silver acetate complexes 2a and 2e were characterised by single crystal X-ray diffraction. The preliminary in vitro antibacterial activity of the NHC–silver complexes 2a–e was investigated against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli using the qualitative Kirby–Bauer disk-diffusion method. The areas of clearance determined for the maximum dose (4.3 μM) range between 1 mm and 7 mm for MSSA and 0 mm and 7 mm for E. coli. All of the newly synthesised silver(I) acetate complexes were tested for their cytotoxicity by MTT based in vitro tests on the human renal cancer cell line Caki-1 and human breast cancer cell line MCF-7 in order to determine their IC50 values.The NHC–silver complexes 2a–e were found to have IC50 values of 3.0 (±0.6), 0.51 (±0.07), 4.2 (±1.2), 9.0 (±0.6), 26 (±2) μM, against the renal cancer cell-line Caki-1 and IC50 values of 2.3 (±0.4), 1.4 (±0.2), 3.0 (±0.5), 3.4 (±1.2) and 14 (±2) μM against the breast cancer cell line MCF-7, respectively. Compared to our lead compound SBC3 (1,3-bisbenzyl-4,5-bisphenyl-imidazole-2-ylium silver(I) acetate) (IC50 value = 14 (±1) μM against Caki-1 and 5.8 (±0.6) μM against MCF-7) these values represent improved cytotoxicity against both cell lines, especially for the silver complexes 2a and 2b. These two compounds are not only more active than SBC3 but also exhibit in the case of 2b a 7 times higher biological activity than cisplatin (IC50 value = 3.3 μM) against Caki-1.Graphical abstractFive NHC silver(I) acetate complexes have been prepared and characterised by spectroscopic methods and X-ray crystallography. The complexes show good to very good activity in their biological assays against cancer cells and pathogenic bacteria.Highlights► Five NHC–silver(I) acetate complexes have been synthesised and characterised. ► Molecular structures of two complexes were determined by X-ray crystallography. ► All compounds were tested for their cytotoxic and antibacterial activity.

Novel Ruthenium(II) and Gold(I) NHC Complexes: Synthesis, Characterization, and Evaluation of Their Anticancer Properties

Co-reporter:Frauke Hackenberg ; Helge Müller-Bunz ; Raymond Smith ; Wojciech Streciwilk ; Xiangming Zhu

Organometallics 2013 Volume 32(Issue 19) pp:5551-5560

Publication Date(Web):September 13, 2013

DOI:10.1021/om400819p

The synthesis, characterization, and biological evaluation of novel Ru(II)- and Au(I)-N-heterocyclic carbenes is reported. The NHC-ruthenium(II) complexes (1–6) were synthesized by reacting the appropriately substituted imidazolium bromides with Ag2O, forming the NHC-silver bromide in situ followed by transmetalation with dimeric p-cymene ruthenium(II) dichloride. In an analogous manner the NHC-gold(I) chloride complexes (NHC-Au(I)Cl) 7–9 were synthesized, utilizing dimethylsulfido gold(I) chloride as the transmetalating agent. The ligand exchange on the NHC-gold(I) chlorides was achieved by either reacting the complexes with silver acetate to yield the NHC-gold(I) acetates (NHC-Au(I)OAc) 10–12 or reacting the NHC-gold(I) chlorides under basic conditions with 2′,3′,4′,6′-tetra-O-acetyl-1-thio-β-d-glucopyranose (SR) to give the NHC-gold(I)-(2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate) complexes (NHC-Au(I)SR) 13–15. The Ru(II)-NHC complex 1 and the Au(I)-NHC complex 9 were characterized by single-crystal X-ray diffraction. Also the IC50 values of these 15 complexes were determined by an MTT-based assay against the human cancer cell lines Caki-1 (renal) and MCF-7 (breast). The Ru(II) complexes 1–6 revealed the following IC50 values against Caki-1 of >500, 94 (±5), 93 (±2), 170 (±20), 39 (±5), and 13 (±2) μM and against MCF-7 of >500, 80 (±15), 19 (±1), 7.1 (±1.2), 2.4 (±0.7), and 7.0 (±1.2) μM, respectively. IC50 values of 67 (±7), 16 (±2), 41 (±1), 31 (±2), 42 (±5), 18 (±1), 14 (±2), 17 (±2), and 58 (±2) μM against Caki-1 and 8.4 (±0.4), 30 (±3), 12 (±1), 23 (±3), 12 (±1), 25 (±3), 6.1 (±1.5), 9.3 (±1.6), and 14 (±2) μM against MCF-7 were found for the Au(I) complexes 7–15.

Synthesis and Cytotoxicity Studies of Silyl-Substituted Titanocene Dichloride Derivatives

Co-reporter:Anthony Deally, Frauke Hackenberg, Grainne Lally, Helge Müller-Bunz, and Matthias Tacke

Organometallics 2012 Volume 31(Issue 16) pp:5782-5790

Publication Date(Web):July 2, 2012

DOI:10.1021/om300227h

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 all six titanocenes were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC50 values. Titanocenes were found to have IC50 values of 139 (±5), 106 (± 4), 127 (±4), 104 (±9), 90 (±6), and 15 (±2) μM.

Novel symmetrically p-benzyl-substituted 4,5-diaryl-imidazole N-heterocyclic carbene-silver(I) acetate complexes – Synthesis and biological evaluation

Co-reporter:Frauke Hackenberg, Grainne Lally, Helge Müller-Bunz, Francesca Paradisi, Daniela Quaglia, Wojciech Streciwilk, Matthias Tacke

Journal of Organometallic Chemistry 2012 717() pp: 123-134

Publication Date(Web):

DOI:10.1016/j.jorganchem.2012.07.006

Novel benzyl-substituted N-heterocyclic carbene–silver acetate complexes: synthesis, cytotoxicity and antibacterial studies

Co-reporter:Siddappa Patil, Anthony Deally, Brendan Gleeson, Helge Müller-Bunz, Francesca Paradisi and Matthias Tacke

Metallomics 2011 vol. 3(Issue 1) pp:74-88

Publication Date(Web):06 Dec 2010

DOI:10.1039/C0MT00034E

From the reaction of 1-methylimidazole (1a), 4,5-dichloro-1H-imidazole (1bII) and 1-methylbenzimidazole (1c) with p-cyanobenzyl bromide (2a), non-symmetrically substituted N-heterocyclic carbene (NHC) [(3a–c)] precursors, 5,6-dimethyl-1H-benzimidazole (1d) and 4,5-diphenyl-1H-imidazole (1e) with p-cyanobenzyl bromide (2a) and benzyl bromide (2b), symmetrically substituted N-heterocyclic carbene (NHC) [(3d–f)] precursors were synthesised. These NHC-precursors were then reacted with silver(I) acetate to yield the NHC–silver complexes (1-methyl-3-(4-cyanobenzyl)imidazole-2-ylidene)silver(I)acetate (4a), (4,5-dichloro-1-(4-cyanobenzyl)-3-methyl)imidazole-2-ylidene)silver(I)acetate (4b), (1-methyl-3-(4-cyanobenzyl)benzimidazole-2-ylidene)silver(I)acetate (4c), (1,3-bis(4-cyanobenzyl)5,6-dimethylbenzimidazole-2-ylidene) silver(I) acetate (4d), (1,3-dibenzyl-5,6-dimethylbenzimidazole-2-ylidene) silver(I) acetate (4e) and (1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene) silver(I) acetate (4f) respectively. Three NHC-precursors 3c–e and four NHC–silver complexes 4b and 4d–f were characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial activity of the NHC-precursors and NHC–silver complexes was investigated against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative Kirby–Bauer disk-diffusion method. NHC–silver complexes have shown very high antibacterial activity compared to the NHC-precursors. All six NHC–silver complexes were tested for their cytotoxicity through MTT based in vitro tests on the human renal-cancer cell line Caki-1 in order to determine their IC50 values. NHC–silver complexes 4a–f were found to have IC50 values of 6.2 (±1.0), 7.7 (±1.6), 1.2 (±0.6), 10.8 (±1.9), 24.2 (±1.8) and 13.6 (±1.0) μM, respectively. These values represent improved cytotoxicity against Caki-1, most notably for 4c, which is a three times more cytotoxic than cisplatin (IC50 value = 3.3 μM) itself.

Synthesis and cytotoxicity studies of achiral azaindole-substituted titanocenes

Co-reporter:Luis Miguel Menéndez Méndez;Anthony Deally;Donal F. O'Shea

Heteroatom Chemistry 2011 Volume 22( Issue 2) pp:148-157

Publication Date(Web):

DOI:10.1002/hc.20668

Abstract

From the reaction of 1-methyl-1 H-pyr-rolo[2,3-b]pyridine (1a),1-(methoxymethyl)-1 H-pyrrolo[2,3-b]pyridine (1b), 1-isopropyl-1 H-pyrrolo[2,3-b]pyridine (1c), and 1-(4-methoxybenzyl)-1 H-pyrrolo[2,3-b]pyridine (1d) under Vilsmeier–Haak conditions, the corresponding aldehydes in position 3 (2a–2d) were synthesized. These aldehydes were transformed in the corresponding fulvenes (3a–3d) by the Knoevenagel condensation and treated with Li[BEt₃H] to obtain the corresponding lithiated cyclopentadienide intermediates (3′a–3′d). These intermediates were, finally transmetallated to titanium with TiCl₄ to yield the 7-azaindol-3-yl-substituted titanocenes bis {[(1-methyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl] cyclopentadienyl} titanium(IV) dichloride (4a), bis{[(1-methoxymethyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV)dichloride (4b), bis{[(1-Isopropyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV) dichloride (4c), and bis{[(4-methoxybenzyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV) dichloride (4d). All the titanocenes had their cytotoxicity investigated through MTT-based preliminary in vitro testing on the Caki-1 cell lines to determinate their IC₅₀ values. Titanocenes 4a–4c were found to have IC₅₀ values of 120 ± 10, 83 ± 13, and 54 ± 12, µM respectively, whereas 4d showed no cytotoxic activity. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:148–157, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20668

Novel Benzyl- or 4-Cyanobenzyl-Substituted N-Heterocyclic (Bromo)(carbene)silver(I) and (Carbene)(chloro)gold(I) Complexes: Synthesis and Preliminary Cytotoxicity Studies

Co-reporter:Siddappa Patil;Anthony Deally;Frauke Hackenberg;Leonard Kaps;Helge Müller-Bunz;Rainer Schobert

Helvetica Chimica Acta 2011 Volume 94( Issue 9) pp:1551-1562

Publication Date(Web):

DOI:10.1002/hlca.201100107

Abstract

N-Heterocyclic carbene (NHC) complexes bromo(1,3-dibenzyl-1,3-dihydro-2H-imidazol-2-ylidene)silver(I) (2a), bromo[1-(4-cyanobenzyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene]silver(I) (2b), and bromo[1-(4-cyanobenzyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-ylidene]silver(I) (2c) were prepared by the reaction of 1,3-dibenzyl-1H-imidazol-3-ium bromide (1a), 3-(4-cyanobenzyl)-1-methyl-1H-imidazol-3-ium bromide (1b), and 3-(4-cyanobenzyl)-1-methyl-1H-benzimidazol-3-ium bromide (1c), respectively, with silver(I) oxide. NHC Complexes chloro(1,3-dibenzyl-1,3-dihydro-2H-imidazol-2-ylidene)gold(I) (3a), chloro[1-(4-cyanobenzyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (3b), and chloro[1-(4-cyanobenzyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-ylidene]gold(I) (3c) were prepared via transmetallation of corresponding (bromo)(NHC)silver(I) complexes with chloro(dimethylsulfido)gold(I). The complex 3a was characterized in two polymorphic forms by single-crystal X-ray diffraction showing two rotamers in the solid state. The cytotoxicities of all three bromo(NHC)silver(I) complexes and three (chloro)(NHC)gold(I) complexes were investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bormide (MTT)-based preliminary in vitro testing on the Caki-1 cell line in order to determine their IC₅₀ values. (Bromo)(NHC)silver(I) complexes 2a–2c and (chloro)(NHC)gold(I) complexes 3a–3c were found to have IC₅₀ values of 27±2, 28±2, 34±6, 10±1, 12±5, and 12±3 μM, respectively, on the Caki-1 cell line.

Towards peptide-substituted titanocene anticancer drugs

Co-reporter:Johannes Zagermann, Anthony Deally, Nils Metzler-Nolte, Helge Müller-Bunz, Denise Wallis, Matthias Tacke

Polyhedron 2011 30(14) pp: 2387-2390

Publication Date(Web):

DOI:10.1016/j.poly.2011.05.036

Novel achiral indole-substituted titanocenes: Synthesis and preliminary cytotoxicity studies

Co-reporter:Anthony Deally, Brendan Gleeson, Helge Müller-Bunz, Siddappa Patil, Donal F. O’Shea, Matthias Tacke

Journal of Organometallic Chemistry 2011 696(5) pp: 1072-1083

Publication Date(Web):

DOI:10.1016/j.jorganchem.2010.10.039

Synthesis, Cytotoxicity and Antibacterial Studies of p-Methoxybenzyl-Substituted and Benzyl-Substituted N-Heterocyclic CarbeneSilver Complexes

Co-reporter:Siddappa Patil;James Claffey;Anthony Deally;Megan Hogan;Brendan Gleeson;Luis Miguel Menéndez Méndez;Helge Müller-Bunz;Francesca Paradisi

European Journal of Inorganic Chemistry 2010 Volume 2010( Issue 7) pp:1020-1031

Publication Date(Web):

DOI:10.1002/ejic.200900889

Abstract

p-Methoxybenzyl-substituted and benzyl-substituted N-heterocyclic carbene (NHC) [(3a–c) and (6a–c)] precursors were synthesised from the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b), and 1H-benzimidazole (1c) with p-methoxybenzyl bromide (2) and benzyl bromide (5). These NHC precursors were then treated with silver(I) acetate to yield the NHC–silver complexes [1,3-bis(4-methoxybenzyl)imidazol-2-ylidene]silver(I) acetate (4a), [4,5-dichloro-1,3-bis(4-methoxybenzyl)imidazol-2-ylidene]silver(I) acetate (4b), [1,3-bis(4-methoxybenzyl)benzimidazol-2-ylidene]silver(I) acetate (4c), (1,3-dibenzylimidazol-2-ylidene)silver(I) acetate (7a), (1,3-dibenzyl-4,5-dichloroimidazol-2-ylidene)silver(I) acetate (7b), and (1,3-dibenzylbenzimidazol-2-ylidene)silver(I) acetate (7c), respectively. The NHC precursor 3c, four NHC–silver complexes 4c and 7a–c were characterised by single-crystal X-ray diffraction method. The preliminary antibacterial activity of all the compounds was studied against Gram-negative bacteria Escherichia coli, and Gram-positive bacteria Staphylococcus aureus using the Kirby–Bauer disk-diffusion method. Almost all the NHC–silver complexes have shown high antibacterial activity compared to the NHC precursors. In addition, the NHC–silver complexes had their cytotoxicity investigated through MTT-based preliminary in vitro testing on the Caki-1 cell lines in order to determine their IC₅₀ values. NHC–silver complexes 4a–c and 7a–c were found to have IC₅₀ values of 7.3 (+/–6), 12.7(+/–3), 25.2 (+/–5), 2.5 (+/–3), 10.8 (+/–4) and 12.5 (+/–4) μM respectively on the Caki-1 cell line.

Synthesis, cytotoxicity and antibacterial studies of symmetrically and non-symmetrically benzyl- or p-cyanobenzyl-substituted N-Heterocyclic carbenesilver complexes

Co-reporter:Siddappa Patil;Anthony Deally;Brendan Gleeson;Helge Müller-Bunz;Francesca Paradisi

Applied Organometallic Chemistry 2010 Volume 24( Issue 11) pp:781-793

Publication Date(Web):

DOI:10.1002/aoc.1702

Abstract

From the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b) and 1H-benzimidazole (1c) with p-cyanobenzyl bromide (2), symmetrically substituted N-heterocyclic carbene (NHC) [(3a–c)] precursors, 1-methylimidazole (5a), 4,5-dichloro-1-methylimidazole (5b) and 1-methylbenzimidazole (5c) with benzyl bromide (6), non-symmetrically substituted N-heterocyclic carbene (NHC) [(7a–c)] precursors were synthesized. These NHCprecursors were then reacted with silver(I) acetate to yield the NHC-silver complexes [1,3-bis(4-cyanobenzyl)imidazole-2-ylidene] silver(I) acetate (4a), [4,5-dichloro-1,3-bis(4-cyanobenzyl)imidazole-2-ylidene] silver(I) acetate (4b), [1,3-bis(4-cyanobenzyl)benzimidazole-2-ylidene] silver(I) acetate (4c), (1-methyl-3-benzylimidazole-2-ylidene) silver(I) acetate (8a), (4,5-dichloro-1-methyl-3-benzylimidazole-2-ylidene) silver(I) acetate (8b) and (1-methyl-3-benzylbenzimidazole-2-ylidene) silver(I) acetate (8c) respectively. The four NHC-precursors 3a–c, 7c and four NHC–silver complexes 4a–c and 8c were characterized by single crystal X-ray diffraction. The preliminary antibacterial activity of all the compounds was studied against Gram-negative bacteria Escherichia coli, and Gram-positive bacteria Staphylococcus aureus using the qualitative Kirby-Bauer disc-diffusion method. All NHC–silver complexes exhibited medium to high antibacterial activity with areas of clearance ranging from 4 to 12 mm at the highest amount used, while the NHC-precursors showed significantly lower activity. In addition, all NHC–silver complexes underwent preliminary cytotoxicity tests on the human renal-cancer cell line Caki-1 and showed medium to high cytotoxicity with IC₅₀ values ranging from 53 ( ± 8) to 3.2 ( ± 0.6) µM. Copyright © 2010 John Wiley & Sons, Ltd.

Synthesis and cytotoxicity studies of novel anion-exchanged Titanocene Y derivatives

Co-reporter:James Claffey;Anthony Deally;Brendan Gleeson;Siddappa Patil

Applied Organometallic Chemistry 2010 Volume 24( Issue 10) pp:675-679

Publication Date(Web):

DOI:10.1002/aoc.1665

Abstract

Starting from the potential anticancer drug candidate Titanocene Y {bis-[(4-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride}, anion exchange experiments were performed using silver malonate (1a) or silver cyclobutane-1,1-malonate (1b) in order to yield bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) malonate (2a) and bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) cyclobutane-1,1-malonate (2b). In addition, Titanocene Y was reacted with salicylic acid (3a) or 3,5-dinitro-salicylic acid (3b) in the presence of diethylamine to synthesize bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) salicylate (4a) or bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) 3,5-dinitro-salicylate (4b). These titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in an MTT-based assay in order to determine their IC50 values. Titanocenes 2a–b and 4a were found to have IC50 values of 74 ( ± 13) µM, 18 ( ± 5) µM and 49 ( ± 11) µM on the LLC-PK cell line, while compound 4b was found to have lost all its cytotoxic activity on this cell line. Copyright © 2010 John Wiley & Sons, Ltd.

Novel benzyl-substituted molybdocene anticancer drugs

Co-reporter:Brendan Gleeson, James Claffey, Anthony Deally, Megan Hogan, Luis Miguel Menéndez Méndez, Helge Müller-Bunz, Siddappa Patil, Matthias Tacke

Inorganica Chimica Acta 2010 Volume 363(Issue 8) pp:1831-1836

Publication Date(Web):5 May 2010

DOI:10.1016/j.ica.2010.02.020

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt3H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to molybdocene using MoCl4 (synthesized in situ) to yield the benzyl-substituted molybdocenes bis-[(p-methoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3c). The molybdocene 3a was characterised by single crystal X-ray diffraction. All three molybdocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the human renal cell line Caki-1 in order to determine their IC50 values and compare them with the corresponding titanocene and vanadocene dichloride derivatives. Molybdocenes 3b–c were found to have the same IC50 values of 290 μM, while 3a yielded a value of 84 μM, respectivelyThree benzyl-substituted molybdocene dichloride complexes were synthesised through the hydridolithiation reaction of appropriately substituted fulvenes with LiBEt3H. Within, the synthesis of the three molybdocene derivatives are reported along with a structural discussion. Additionally, the compounds were tested for their anticancer activity.

Synthesis, Cytotoxicity and Antibacterial Studies of Novel Symmetrically and Nonsymmetrically 4-(Methoxycarbonyl)benzyl-Substituted N-Heterocyclic CarbeneSilver Acetate Complexes

Co-reporter:Siddappa Patil;Karolin Dietrich;Anthony Deally;Brendan Gleeson;Helge Müller-Bunz;Francesca Paradisi

Helvetica Chimica Acta 2010 Volume 93( Issue 12) pp:2347-2364

Publication Date(Web):

DOI:10.1002/hlca.201000310

Abstract

From the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b), 1H-benzimidazole (1c), 1-methyl-1H-imidazole (1d), and 1-methyl-1H-benzimidazole (1f) with methyl 4-(bromomethyl)benzoate (2), symmetrically and nonsymmetrically 4-(methoxycarbonyl)benzyl-substituted N-heterocyclic carbene (NHC) precursors, 3a–3f, were synthesized. These NHC precursors were then reacted with silver(I) acetate (AgOAc) to yield the NHC–silver acetate complexes (acetato-κO){1,3-bis[4-(methoxycarbonyl)benzyl]imidazol-2-ylidene}silver (4a), (acetato-κO){4,5-dichloro-1,3-bis[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-imidazol-2-yl}silver (4b), (acetato-κO){1,3-bis[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-benzimidazol-2-yl}silver (4c), (acetato-κO){1-[4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-imidazol-2-yl}silver (4d), (acetato-κO){4,5-dichloro-1-[4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-imidazol-2-yl}silver (4e), and (acetato-κO){1-[4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-benzimidazol-2-yl}silver (4f), respectively. The three NHC–AgOAc complexes 4a, 4c, and 4d were characterized by single-crystal X-ray diffraction. All compounds studied in this work were preliminarily screened for their antimicrobial activities in vitro against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative disk-diffusion method. All NHC–AgOAc complexes exhibited weak-to-medium antibacterial activity with areas of clearance ranging from 4 to 7 mm at the highest amount used, while the NHC precursors showed significantly lower activity. In addition, NHC–AgOAc complexes 4a and 4b, and 4d–4f exhibited in preliminary cytotoxicity tests on the human renal-cancer cell line Caki-1 medium-to-high cytotoxicities with IC₅₀ values ranging from 3.3±0.4 to 68.3±1 μM.

Synthesis and Preliminary Cytotoxicity Studies of Achiral Indolyl-Substituted Titanocenes

Co-reporter:Megan Hogan, Brendan Gleeson and Matthias Tacke

Organometallics 2010 Volume 29(Issue 4) pp:1032-1040

Publication Date(Web):January 28, 2010

DOI:10.1021/om901031m

From the reaction of various 6-indolylfulvenes (1a−f) with Super Hydride (LiBEt3H), followed by transmetalation with titanium tetrachloride (TiCl4), six indolyl-substituted titanocenes, bis[(1-methylindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3a), bis[(1-methyl-5-methoxyindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3b), a dihydrochloride derivative of bis[(1-methyl-3-dimethylaminomethylindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3c), bis[(1-methylindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3d), bis[(1-methyl-5-methoxyindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3e), and bis[(1-methylmethoxyindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3f), were obtained. The six titanocenes 3a−f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC50 values. Titanocenes 3a−f were found to have IC50 values of 47 (±9), 15 (±2), 8.2 (±1.9), 21 (±5), 11 (±1), and 170 (±40) μM, respectively.

Synthesis and preliminary cytotoxicity studies of achiral pyrrolyl-substituted titanocenes

Co-reporter:Anthony Deally, James Claffey, Brendan Gleeson, Megan Hogan, Helge Müller-Bunz, Siddappa Patil, Donal F. O’Shea, Matthias Tacke

Polyhedron 2010 29(12) pp: 2445-2453

Publication Date(Web):

DOI:10.1016/j.poly.2010.05.018

Benzyl-substituted titanocene dichloride anticancer drugs: From lead to hit

Co-reporter:James Claffey, Helge Müller-Bunz, Matthias Tacke

Journal of Organometallic Chemistry 2010 695(18) pp: 2105-2117

Publication Date(Web):

DOI:10.1016/j.jorganchem.2010.05.025

Antitumor activity of vanadocene Y and its selenocyanate derivative in xenografted caki-1 tumors in mice

Co-reporter:Iduna Fichtner, James Claffey, Anthony Deally, Brendan Gleeson, Megan Hogan, Maria Rivera Markelova, Helge Müller-Bunz, Holger Weber, Matthias Tacke

Journal of Organometallic Chemistry 2010 695(8) pp: 1175-1181

Publication Date(Web):

DOI:10.1016/j.jorganchem.2010.01.026

Synthesis and preliminary cytotoxicity studies of indole-substituted vanadocenes

Co-reporter:Brendan Gleeson;Megan Hogan;Helge Müller-Bunz

Transition Metal Chemistry 2010 Volume 35( Issue 8) pp:973-983

Publication Date(Web):2010 November

DOI:10.1007/s11243-010-9419-1

From the reaction of various 6-indolylfulvenes (1a–1e) with Super Hydride (LiBEt3H), followed by transmetallation with vanadium tetrachloride (VCl4), six indole-substituted vanadocenes; bis-[(1-methylindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3a), bis-[(1-methyl-5-methoxyindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3b), bis-[(1-methylindol-3-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3c), bis-[(1-methyl-5-methoxyindol-3-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3d), a dihydrochloride derivative of bis-[(1-methyl-3-dimethylaminomethylindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3e), and bis-[(1-methyl-5-methoxyindol-3-yl)methylcyclopentadienyl] vanadium (IV) diselenocyanate (3f), were synthesised. The six vanadocenes 3a–f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC50 values. Vanadocenes 3a–f were found to have IC50 values of 48 (±4), 24 (±4), 9.2 (±1.8), 2.5 (±0.8), 2.3 (±0.7) and 22 (±7) μM.

Pseudo-halide derivatives of titanoceneY: synthesis and cytotoxicity studies

Co-reporter:James Claffey, Anthony Deally, Brendan Gleeson, Megan Hogan, Luis Miguel Menéndez Méndez, Helge Müller-Bunz, Siddappa Patil, Denise Wallis and Matthias Tacke

Metallomics 2009 vol. 1(Issue 6) pp:511-517

Publication Date(Web):02 Sep 2009

DOI:10.1039/B911753A

The well-known anticancer drug candidate bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (TitanoceneY) was reacted with sodium azide or potassium cyanate, thiocyanate or selenocyanate in order to give pseudo-halide analogues 2a–d of TitanoceneY. 2b and 2c were characterised by single crystal X-ray diffraction, which confirmed the expected nitrogen binding of the cyanate and thiocyanate to the titanium centre. All four titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in an MTT based assay in order to determine their IC50 values. Titanocenes2a–d were found to have IC50 values of 24 (±8) μM, 101 (±14) μM, 54 (±21) μM and 27 (±4) μM respectively. All four titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride and 2a and 2d showed similiar cytotoxic behaviour to TitanoceneYin vitro.

Synthesis and Cytotoxicity Studies of Fluorinated Derivatives of Vanadocene Y

Co-reporter:Brendan Gleeson;James Claffey;Anthony Deally;Megan Hogan;Luis Miguel Menéndez Méndez;Helge Müller-Bunz;Siddappa Patil;Denise Wallis

European Journal of Inorganic Chemistry 2009 Volume 2009( Issue 19) pp:2804-2810

Publication Date(Web):

DOI:10.1002/ejic.200900297

Abstract

From the reaction of 6-(2-fluoro-4-methoxyphenyl)fulvene (1a), 6-(3-fluoro-4-methoxyphenyl)fulvene (1b) and 6-[4-(trifluoromethoxy)phenyl]fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to vanadium with VCl₄ to yield the benzyl-substituted vanadocenes bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3a), bis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3b), and bis[(4-trifluoromethoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3c). The three vanadocenes 3a–c were characterised by single-crystal X-ray diffraction. All three vanadocenes had their cytotoxicity investigated through MTT-based preliminary in-vitro testing on the LLC-PK and Caki-1 cell lines in order to determine their IC₅₀ values. Vanadocenes 3a–c were found to have IC₅₀ values of 6.0 (+/–4), 35 (+/–7) and 13 (+/–3) μM on the LLC-PK cell line and IC₅₀ values of 78 (+/–11), 18 (+/–16) and 2.2 (+/–0.5) μM on the Caki-1 cell line respectively. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Novel benzyl-substituted vanadocene anticancer drugs

Co-reporter:Brendan Gleeson, James Claffey, Megan Hogan, Helge Müller-Bunz, Denise Wallis, Matthias Tacke

Journal of Organometallic Chemistry 2009 694(9–10) pp: 1369-1374

Publication Date(Web):

DOI:10.1016/j.jorganchem.2008.12.033

Novel zirconocene anticancer drugs?

Co-reporter:Denise Wallis, James Claffey, Brendan Gleeson, Megan Hogan, Helge Müller-Bunz, Matthias Tacke

Journal of Organometallic Chemistry 2009 694(6) pp: 828-833

Publication Date(Web):

DOI:10.1016/j.jorganchem.2008.08.020

Fluorinated Derivatives of Titanocene Y: Synthesis and Cytotoxicity Studies

Co-reporter:James Claffey;Brendan Gleeson;Megan Hogan;Helge Müller-Bunz;Denise Wallis

European Journal of Inorganic Chemistry 2008 Volume 2008( Issue 26) pp:4074-4082

Publication Date(Web):

DOI:10.1002/ejic.200800504

Abstract

From the reaction of Super Hydride (LiBEt₃H) with 6-(2-fluoro-4-methoxyphenyl)fulvene (1a), 6-(4-trifluoromethoxyphenyl)fulvene (1b), and 6-(3-fluoro-4-methoxyphenyl)fulvene (1c) lithiated cyclopentadienide intermediates 2a–c were synthesised. These intermediates were then transmetallated to titanium with TiCl₄ to give the benzyl-substituted titanocenes bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3a), bis[(4-trifluoromethoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3b) andbis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV)dichloride (3c). The three titanocenes 3a–c were characterised by single-crystal X-ray diffraction. Preliminary in vitro cell tests were performed on the titanocenes on the LLC-PK (long-lasting cells–pig kidney) cell line in order to determine the cytotoxicity of these compounds presented in this paper. The titanocenes 3a and 3b had their cytotoxicity inhibitory concentration (IC₅₀) values determined to be 6.0 and 7.3 μM, respectively. The cytotoxicity value of 3c could not be determined accurately due to solubility problems of the compound under standard test conditions. All three titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride, whereas titanocenes 3a and 3b show threefold cytotoxicity improvement in comparison to previous class leader titanocene Y. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Oxali-TitanoceneY: A Potent Anticancer Drug

Co-reporter:James Claffey;Megan Hogan;Helge Müller-Bunz Dr.;Clara Pampillón Dr.

ChemMedChem 2008 Volume 3( Issue 5) pp:729-731

Publication Date(Web):

DOI:10.1002/cmdc.200700302

Novel achiral titanocene anti-cancer drugs synthesised from bis-N,N-dimethylamino fulvene and lithiated heterocyclic compounds

Co-reporter:Clara Pampillón;James Claffey;Megan Hogan

BioMetals 2008 Volume 21( Issue 2) pp:197-204

Publication Date(Web):2008 April

DOI:10.1007/s10534-007-9108-5

From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC50-values obtained were of 240, and 270 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC50-value of 36 μM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC50 = 5.5 μM) and almost ten times less cytotoxic than cisplatin, which showed an IC50-value of 3.3 μM, when tested on the LLC-PK cell line. Bis-(bis- (N,N-dimethylamino)-2-(N′-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride, {η5-C5H4-CH[N(CH3)2]2[C5H3NCH3]}2TiCl2 was synthesised starting from 6-bis-(N,N-dimethylamino) fulvene and 2-N-methylpyrrolyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells.

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

Co-reporter:Nigel J. Sweeney;James Claffey;Helge Müller-Bunz;Clara Pampillón;Katja Strohfeldt

Applied Organometallic Chemistry 2007 Volume 21(Issue 2) pp:

Publication Date(Web):18 DEC 2006

DOI:10.1002/aoc.1177

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 1a with titanium dichloride. The diarylmethyl substituted titanocene bis(di-(benzo[1,3]dioxole)-5-methylcyclopentadienyl) titanium(IV) dichloride (2c) was synthesized by reacting 1a 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 × 10⁻⁴, 1.6 × 10⁻⁴ and 7.6 × 10⁻⁵M, 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 © 2006 John Wiley & Sons, Ltd.

Proliferative and antiproliferative effects in substituted titanocene anticancer drugs

Co-reporter:Katja Strohfeldt;Helge Müller-Bunz;Clara Pampillón

Transition Metal Chemistry 2007 Volume 32( Issue 7) pp:971-980

Publication Date(Web):2007 October

DOI:10.1007/s11243-007-0265-8

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.When the benzyl-substituted titanocene (8a) was tested against pig kidney cells (LLC-PK) an anti-proliferative effect, resulting in an IC50 value of 25 µM, was observed. This IC50 value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. The ansa-titanocene (6b) showed surprisingly, when tested on the same cell line, a proliferative effect.

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and indolyl-substituted titanocene anti-cancer drugs

Co-reporter:Clara Pampillón;James Claffey;Megan Hogan;Katja Strohfeldt

Transition Metal Chemistry 2007 Volume 32( Issue 4) pp:434-441

Publication Date(Web):2007 May

DOI:10.1007/s11243-006-0183-1

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 TiCl4 resulting in dimethylamino-functionalised titanocenes (5a–c). When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 37 and 71 μM for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC50 value of 8.4 μM is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself.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.Open image in new window

Dimethylamino-functionalised and N-heteroaryl-substituted titanocene anticancer drugs: synthesis and cytotoxicity studies

Co-reporter:Thomas Hickey;James Claffey;Eoin Fitzpatrick;Megan Hogan

Investigational New Drugs 2007 Volume 25( Issue 5) pp:425-433

Publication Date(Web):2007 October

DOI:10.1007/s10637-007-9061-8

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 TiCl4 resulting in dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 13, and 63 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper (5a) with an IC50 value of 6.8 μM is found to be almost as cytotoxic as cis-platin, which showed an IC50 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.

Glycol Methyl Ether and Glycol Amine Substituted Titanocenes as Antitumor Agents

Co-reporter:Katja Strohfeldt;Helge Müller-Bunz;Clara Pampillón;Nigel J. Sweeney

European Journal of Inorganic Chemistry 2006 Volume 2006(Issue 22) pp:

Publication Date(Web):20 SEP 2006

DOI:10.1002/ejic.200600586

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)

Heteroaryl substituted titanocenes as potential anti-cancer drugs

Co-reporter:Nigel Sweeney, William M. Gallagher, Helge Müller-Bunz, Clara Pampillón, Katja Strohfeldt, Matthias Tacke

Journal of Inorganic Biochemistry 2006 Volume 100(Issue 9) pp:1479-1486

Publication Date(Web):September 2006

DOI:10.1016/j.jinorgbio.2006.04.006

From the reaction of Super Hydride (LiBEt3H) with 6-(furyl)fulvene (1a), 6-(thiophenyl)fulvene (1b) or 6-(N-methyl-pyrrole)fulvene (1c) the corresponding lithium cyclopentadienide intermediates (2a–c) were obtained. These intermediates were reacted with titanium tetrachloride and bis-[(furyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3a) and bis-[(thiophenyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3b) and bis-[(N-methylpyrrole-2-cyclopentadienylmethane)] titanium(IV) dichloride (3c) were obtained and subsequently characterised by X-ray crystallography. When titanocenes 3a–c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 1.6 × 10−4 M, 1.5 × 10−4 M and 9.1 × 10−4 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared to their corresponding ansa substituted analogues and also in comparison to unsubstituted titanocene dichloride.

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

Co-reporter:Clara Pampillón, Nigel J. Sweeney, Katja Strohfeldt, Matthias Tacke

Inorganica Chimica Acta 2006 Volume 359(Issue 12) pp:3969-3975

Publication Date(Web):1 September 2006

DOI:10.1016/j.ica.2006.05.021

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a–c). Titanocenes (5a–c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC50) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.Bis-[di-(2-thiophenyl)methylcyclopentadienyl] titanium (IV) dichloride was synthesised starting from 6-(2-thiophenyl) fulvene and 2-thiophenyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells.

Heteroaryl substituted ansa-titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Co-reporter:Franz-Josef K. Rehmann;Laurence P. Cuffe;Oscar Mendoza;Dilip K. Rai;Nigel Sweeney;Katja Strohfeldt;William M. Gallagher

Applied Organometallic Chemistry 2005 Volume 19(Issue 3) pp:

Publication Date(Web):14 FEB 2005

DOI:10.1002/aoc.864

Starting from 2-furylfulvene (1a), 2-thiophenylfulvene (1b), and 1-methyl-2-pyrrolylfulvene (1c), [1,2-di(cyclopentadienyl)-1,2-di-(2-furyl)ethanediyl] titanium dichloride (2a), [1,2-di(cyclopentadienyl)-1,2-di-(2-thiophenyl)ethanediyl] titanium dichloride (2b), and [1,2-di(cyclopentadienyl)-1,2-bis-(1-methyl-2-pyrrolyl)ethanediyl] titanium dichloride (2c) were synthesized. When titanocenes (2a–c) were tested against pig kidney carcinoma cells (LLC-PK), inhibitory concentrations (50%) of 4.5 × 10⁻⁴M, 2.9 × 10⁻⁴M and 2.0 × 10⁻⁴M respectively were observed. Copyright © 2005 John Wiley & Sons, Ltd.

The cocondensation reaction of lithium atoms and anisole: an experimental and theoretical study of the reaction pathway

Co-reporter:Oscar Mendoza, Laurence P. Cuffe, Franz-Josef K. Rehmann, Matthias Tacke

Journal of Organometallic Chemistry 2005 Volume 690(Issue 6) pp:1511-1522

Publication Date(Web):15 March 2005

DOI:10.1016/j.jorganchem.2004.12.016

The cocondensation reaction of lithium atoms and pure anisole leads to an ortho CH activation and the formation of lithium hydride. This simple two-component system allows the investigation of the reaction mechanism with included donor molecules. Therefore two anisole and one dilithium molecule, which was identified in an earlier spectroscopic study, were considered for the reaction pathway calculations.Firstly, two intermediates can be found along the reaction pathway, which show the reaction before and after the critical CH activation step. Secondly, a low-lying transition state can be identified, which allows the carbon hydrogen bond to be broken with an activation energy of less than 20 kcal/mol instead of more than 100 kcal/mol, if a free radical mechanism is employed. All calculations were performed at the B3LYP/6-31G** level of theory.The cocondensation reaction of lithium atoms and pure anisole leads to an ortho CH activation and the formation of lithium hydride. This simple two-component system allows for this detailed DFT investigation of the reaction mechanism with included donor molecules.

Cocondensation reactions of nitrogen-containing heterocycles with lithium atoms at 77 K

Co-reporter:Oscar Mendoza, Helge Müller-Bunz, Matthias Tacke

Journal of Organometallic Chemistry 2005 Volume 690(Issue 14) pp:3357-3365

Publication Date(Web):15 July 2005

DOI:10.1016/j.jorganchem.2005.04.017

Lithium atoms were cocondensed with aromatic nitrogen-containing heterocycles in the presence of THF at 77 K. The reaction products in the case of the heterocyclic five-membered rings (imidazole) resulted in a C–H bond activation and led to the corresponding aryl lithium compound. Other heterocycles such as pyridine and pyrimidine led to the formation of a non-lithiated aromatic product, in which the parent compound was dimerised with hydrogen being lost. A special case was found, when substituted pyridines carrying methyl and methoxy groups were reacted under these cocondensation conditions. Here a dimeric species is found again, but the product is dilithiated at the two nitrogen atoms and two hexadienes rings were found instead of an aromatic system. DFT calculations at the B3LYP/6-31G** level of theory were carried out in order to interpret the pathways of the cocondensation reactions and identify the possible intermediates involved. In all reactions σ-complexes between lithium molecules and the heterocycles were found as stable intermediates.Lithium atoms were cocondensed with aromatic nitrogen-containing heterocycles in the presence of THF. The reaction led to a variety of products depending on the heterocyclic compound used. C–H activation, dimerisation of reactants and dimerised hexadienes were the main products found.

Novel benzyl substituted titanocene anti-cancer drugs

Co-reporter:Nigel J. Sweeney, Oscar Mendoza, Helge Müller-Bunz, Clara Pampillón, Franz-Josef K. Rehmann, Katja Strohfeldt, Matthias Tacke

Journal of Organometallic Chemistry 2005 Volume 690(21–22) pp:4537-4544

Publication Date(Web):1 November 2005

DOI:10.1016/j.jorganchem.2005.06.039

From the novel reaction of Super Hydride (LiB(Et)3H) with 6-(p-N,N-dimethylanilinyl)fulvene (1a) or 6-(p-methoxyphenyl)fulvene (1b) the corresponding lithium cyclopentadienide intermediates (2a, 2b) were obtained. When reacted with TiCl4, bis-[(p-dimethylaminobenzyl)cyclopentadienyl]titanium (IV) dichloride (3a) and bis-[(p-methoxybenzyl)cyclopentadienyl]titanium (IV) dichloride (3b) were obtained. Titanocene 3a was reacted with an ethereal solution of HCl, by which its dihydrochloride derivative (3c) was formed and isolated. Titanocenes 3b and 3c were characterised by X-ray crystallography. When the titanocenes 3a–c were tested against pig kidney carcinoma (LLC-PK) cells inhibitory concentrations (IC50) of 1.2 × 10−4 M, 2.1 × 10−5 M and 9.0 × 10−5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, most notably for 3b (Titanocene Y), which is a hundred times more cytotoxic than titanocene dichloride itself.Bis-[(p-methoxybenzyl)cyclopentadienyl]titanium (IV) dichloride is a promising candidate for an anti-cancer drug and was synthesised starting from 6-(p-methoxyphenyl)fulvene and Super Hydride. Herein, we present the synthesis and X-ray structure of the titanocene followed by MTT-based cytotoxicity tests on pig kidney carcinoma (LLC-PK) cells.

Methoxy-phenyl substituted ansa-titanocenes as potential anti-cancer drugs derived from fulvenes and titanium dichloride

Co-reporter:Matthias Tacke, Laurence P. Cuffe, William M. Gallagher, Ying Lou, Oscar Mendoza, Helge Müller-Bunz, Franz-Josef K. Rehmann, Nigel Sweeney

Journal of Inorganic Biochemistry 2004 Volume 98(Issue 12) pp:1987-1994

Publication Date(Web):December 2004

DOI:10.1016/j.jinorgbio.2004.09.001

Starting from 6-(4′-methoxyphenyl)fulvene (1a), 6-(2′,4′,6′-trimethoxyphenyl)fulvene (1b), or 6-(3′,5′-dimethoxyphenyl)fulvene (1c), [1,2-di(cyclopentadienyl)-1,2-di(4′-methoxyphenyl)-ethanediyl] titanium dichloride (2a), [1,2-di(cyclopentadienyl)-1,2-bis(2′,4′,6′-trimethoxyphenyl)-ethanediyl] titanium dichloride (2b), and [1,2-di(cyclopentadienyl)-1,2-bis(3′,5′-dimethoxyphenyl)-ethanediyl] titanium dichloride (2c) were synthesised. When titanocenes 2a–c were tested against pig kidney carcinoma cells (LLC-PK) inhibitory concentrations (IC50) of 2.8 × 10−4, 3.6 × 10−4 and 2.1 × 10−4 M, respectively, were observed.

Cocondensation Reactions of Five-Membered Heterocycles with Lithium Atoms at 77 K

Co-reporter:Oscar Mendoza;Franz-Josef K. Rehmann;Laurence P. Cuffe

European Journal of Inorganic Chemistry 2004 Volume 2004(Issue 22) pp:

Publication Date(Web):1 OCT 2004

DOI:10.1002/ejic.200400423

Lithium atoms were cocondensed with eight aromatic five-membered heterocycles in the presence of THF at 77 K. In the case of the oxygen- and sulfur-containing heterocycles (furans and thiophenes), the reaction resulted in C−H bond activation and led to the corresponding aryllithium compound. The other heterocycles (pyrroles) failed to react with lithium atoms in the presence of THF. A special case was found when oxazole was reacted under these cocondensation conditions; here a dilithiated product was obtained. DFT (B3LYP/6-31G**) calculations were carried out in order to interpret the pathways of the reactions and the possible intermediates. For all the reactions π- and σ-complexes between lithium clusters and the heterocycles were found as stable intermediates. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Novel derivatives of ansa-titanocenes procured from 6-phenylfulvene: a combined experimental and theoretical study

Co-reporter:Shona Fox, John P Dunne, Matthias Tacke, John F Gallagher

Inorganica Chimica Acta 2004 Volume 357(Issue 1) pp:225-234

Publication Date(Web):9 January 2004

DOI:10.1016/S0020-1693(03)00496-1

The previously prepared trans-[(1,2-diphenyl-1,2-dicyclopentadienyl)ethanediyl] titanium(IV) dichloride, [1,2-(Ph)2C2H2{η5-C5H4}2]Ti(Cl)2, was synthesised using an alternative procedure, from which its crystal structure was determined. Using this compound, a variety of other ansa-titanocene derivatives were synthesised by replacement of the chloride ligands with selected substituents. Thus RTi(X)(Y) systems where R=1,2-(Ph)2C2H2η5-C5H42; X=Y=CH3; X=CH3, Y=Cl; X=Y=NCS; X=Y=NCO; X=Y=OPh and (X/Y)=O have been synthesised and characterised. DFT calculations were performed on the complexes trans-[(1,2-diphenyl-1,2-dicyclopentadienyl)-ethanediyl] titanium(IV) dichloride, bis-(6,6-diphenylfulvene)titanium and bis-(6,6-diphenylfulvene)iron. This demonstrated the role that the metal centre plays in their formation, generating either an ansa-metallocene, a ‘tucked in’ fulvene complex or a metallocene coordinating fulvene anions.Different bonding modes (a, b, c) in metallocenes.

Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Co-reporter:Matthias Tacke, Lorcan T. Allen, Laurence Cuffe, William M. Gallagher, Ying Lou, Oscar Mendoza, Helge Müller-Bunz, Franz-Josef K. Rehmann, Nigel Sweeney

Journal of Organometallic Chemistry 2004 Volume 689(Issue 13) pp:2242-2249

Publication Date(Web):1 July 2004

DOI:10.1016/j.jorganchem.2004.04.015

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC50) of 2.7 × 10−4 and 1.9 × 10−4 M, respectively, were observed.This paper reports the synthesis of four novel [(1,2-diaryl-1,2-dicyclopentadienyl)-ethanediyl] titanium dichlorides and dithiocyanates. When tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC50) of 2.7 × 10−4 and 1.9 × 10−4 M, respectively, were observed for the best derivative.

Co-Condensation Reactions of Substituted Aromatic Compounds with Lithium Atoms at 77 K

Co-reporter:John P. Dunne;Matthias Bockmeyer

European Journal of Inorganic Chemistry 2003 Volume 2003(Issue 3) pp:

Publication Date(Web):16 JAN 2003

DOI:10.1002/ejic.200390065

Lithium atoms were co-condensed with +I-substituted benzene derivatives like trimethyl(phenyl)silane and tert-butylbenzene in the presence of THF at 77 K, which resulted in C−H bond activation, to produce the aryllithium compound as well as the coupling of the substituted phenyl radicals. Other +I-substituted benzene derivatives like xylene and mesitylene failed to react with lithium atoms in the presence of THF. Oxygen and nitrogen donor substituted benzene derivatives (anisole, N,N-dimethylaniline, and N,N-dimethylbenzylamine) showed activation of the ortho C−H bond when co-condensed with lithium atoms in the presence of THF. However, when thioanisole was co-condensed with lithium atoms and THF, a C−S bond cleavage occurred instead. These results were interpreted with the aid of DFT calculations, which show π- and σ-complexes between the lithium clusters and benzene derivatives as reactive intermediates. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Synthesis and Structural Characterisation of a Novel Chiral ansa-Cobaltocenium Hexafluorophosphate

Co-reporter:Shona Fox;John P. Dunne;Dieter Schmitz;Richard Dronskowski

European Journal of Inorganic Chemistry 2002 Volume 2002(Issue 11) pp:

Publication Date(Web):14 OCT 2002

DOI:10.1002/1099-0682(200211)2002:11<3039::AID-EJIC3039>3.0.CO;2-0

trans-[(1,2-Diphenyl-1,2-dicyclopentadienyl)ethanediyl]cobalt(III) hexafluorophosphate (1) was synthesised and its structure derived by X-ray crystallography and spectroscopic methods in conjunction with theoretical calculations. To gain an insight into the effect of these bridging atoms and the exocyclic substituents on the sandwich structure, a study was undertaken in which comparisons were drawn between this ansa-cobaltocenium ion and other previously reported structurally characterised metallocenes and ansa-metallocenes. DFT calculations were also performed to provide further data for this analysis, including reaction energies for the formation of, and breaking of, the bridging C−C bond to ascertain the extent to which this moiety imposes strain on the system. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A study of the reduction of substituted fulvenes using spectro-electrochemistry and ab initio theory

Co-reporter:M Tacke, S Fox, L Cuffe, J.P Dunne, F Hartl, T Mahabiersing

Journal of Molecular Structure 2001 Volume 559(1–3) pp:331-339

Publication Date(Web):9 January 2001

DOI:10.1016/S0022-2860(00)00710-9

Nine substituted fulvenes have been investigated for their synthetic suitability in the production of ansa-metallocenes. Results obtained from experimental methods, including cyclic voltammetry and spectro-electrochemistry, are combined with DFT calculations. This gives additional structural and spectroscopic information, as well as bonding parameters for fulvenes and their radical anions which are the key intermediate in the reaction. From these results, it can be deduced that certain aryl substituted fulvenes and benzofulvenes are promising synthons for ansa-metallocenes.

Carbonyl and Benzene Complexes of Lithium: Transition-Metal-Like Behaviour of Lithium in Organolithium Compounds

Co-reporter:Matthias Tacke

European Journal of Inorganic Chemistry 1998 Volume 1998(Issue 5) pp:

Publication Date(Web):7 DEC 1998

DOI:10.1002/(SICI)1099-0682(199805)1998:5<537::AID-EJIC537>3.0.CO;2-1

Complexes of CO and aromatic compounds were believed to be an exclusive domain of transition metals caused by their ability of backbonding to these ligands. But recently, (benzene)lithium and (carbonyl)lithium complexes were characterized by X-ray structure analysis and IR spectoscopy. In order to determine geometries of the complexes and the bonding energies of the benzene and CO molecule to the organolithium starting compound suitable models were chosen in combination with high-level ab initio calculations. For the carbonyl derivative a reaction enthalpy of −8 kcal/mol was found while the interaction with benzene reached unexpectedly −21 kcal/mol. This underlines the ability of lithium to act like a transition metal in subcoordinated organyl compounds without having d orbitals available for bonding.