Adelheid Hagenbach

NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents.

A series of novel neutral NHC gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biological effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing aromatic rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position (5d) increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidation state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50=374-1505 nM) distinctly lower than auranofin (EC50=18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.

A click approach to structurally diverse conjugates containing a central di-1,2,3-triazole metal chelate.

Assemble & chelate: Click chemistry enables the efficient and selective synthesis of structurally diverse conjugates containing a central di‐1,2,3‐triazole chelator for complexation with [99mTc(CO)3]+. Use of appropriate building blocks allows the modulation of pharmacological relevant characteristics of the conjugate, or the introduction of secondary probes suitable for imaging modalities other than single photon emission computed tomography (SPECT).

Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole.

A novel class of silver N-heterocyclic carbene complexes (5a-f) were synthesized in high yield by reacting silver(I) oxide with 4,5-diarylimidazolium halides (4a-f). The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) (5c) by crystal structure analysis. The X-ray structure indicated a three-dimensional coordination polymer with a repeating unit consisting of a C(carben)-Ag(2)-Br(2)-C(carben) cluster. Pharmacological investigations revealed that all silver complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compound 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacological investigations were performed with selected compounds on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.

Synthesis, characterization and in vitro antitumour activity of a series of novel platinum(II) complexes bearing Schiff base ligands.

A series was neutral platinum(II) complexes bearing OCH(3)- or F-substituted 3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes (diarylsalenes) were synthesized and tested for in vitro antitumour activity. The growth inhibitory effects depended on the configuration and the substitution pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene]platinum(II) (1-Pt) reduced the cell growth of MCF-7 (IC(50) = 7.6 μM) and MDA-MB 231 cells (IC(50) = 10.0 μM), but was inactive against HT-29 cells at the used concentration range (IC(50) > 20 μM). The change of the configuration (meso → d,l) at the 1,2-diimino-1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). Complex 10-Pt (6-F: IC(50)(MCF-7) = 1.5 μM, IC(50)(MDA-MB 231) = 1.3 μM, IC(50) (HT-29) = 2.6 μM) was as active as cisplatin (IC(50)(MCF-7) = 1.6 μM, IC(50)(MDA-MB 231) = 1.5 μM, IC(50)(HT-29) = 4.1 μM).

Organometallic [Re(CO)3]+ and [Re(CO)2(NO)]2+ Labeled Substrates for Human Thymidine Kinase 1

Thymidine was functionalized at position N3 with a tridentate iminodiacetic acid chelating system and a potentially tetradentate mercaptoethyliminodiacetic acid chelating system. Spacers of different lengths (ethyl and butyl) were introduced between the chelators and thymidine. The derivatives were labeled with the [Re(CO)(2)(NO)](2+) and [Re(CO)(3)](+) cores to give isostructural complexes with different overall charges. All complexes were analyzed by NMR, MS, and IR, and in addition, the X-ray structure of a [Re(CO)(2)(NO)](2+) labeled thymidine derivative functionalized at the N3 position was solved. The ligands incorporating the potentially tetradentate mercaptoethyliminodiacetic acid chelating system coordinated tridentately through iminodiacetic acid to both the [Re(CO)(2)(NO)](2+) core and the [Re(CO)(3)](+) core. This was surprising given that the reaction of [NEt(4)][Re(CO)(2)(NO)Br(3)] with the model ligand ethylmercaptoethyliminodiacetic acid led to dissociation of a carbonyl ligand and formation of a monocarbonyl-mononitrosyl complex, as confirmed by X-ray structure analysis. All of the organometallic thymidine derivatives were substrates for human thymidine kinase 1, a key enzyme in (cancer) cell proliferation. Neutral [Re(CO)(2)(NO)](2+) labeled thymidine derivatives revealed substrate activity ranging from 24 to 40%, and the structurally analogous anionic [Re(CO)(3)](+) labeled thymidine derivatives from 20 to 38% compared with the natural substrate thymidine.

Synthese und Struktur von Komplexen mit Nitridobrücken zwischen Rhenium und Zink

Die Reaktion von [ReNCl2(PMePh)3] mit ZnX2 (X = Cl, Br) in CH2Cl2 ergibt die Vierkernkomplexe [(Me2PhP)3X2Re≡N–ZnX2]2. Im Fall der Umsetzung mit ZnBr2 kommt es zu einem Austausch der am Re-Atom gebundenen Halogenatome. [(Me2PhP)3Cl2Re≡N–ZnCl2]2 (1) kristallisiert triklin mit einem zentrosymmetrischen Vierkernkomplex in der Elementarzelle. [(Me2PhP)3Br2Re≡N–ZnBr2]2 (2) bildet trikline Kristalle der Zusammensetzung 2 · 2 CH2Cl2. In den analog aufgebauten, zentrosymmetrischen Vierkernkomplexen koordinieren zwei [ReNX2(PMe2Ph)3]-Komplexe mit ihrem terminalen Nitridoliganden die Zn-Atome einer zentralen XZn(μ-X)2ZnX-Einheit. Die resultierenden Nitridobrucken Re≡N–Zn sind linear (Re–N–Zn = 178,4° (1) und 178,0° (2)) und mit Re–N = 170 pm und Zn–N = 199 pm (1) sowie Re–N = 167 pm und Zn–N = 201 pm (2) stark asymmetrisch. Bei der Umsetzung von [ReNCl2(PMe2Ph)3] mit ZnI2 in CH2Cl2 entsteht vermutlich primar [(Me2PhP)3ClIRe≡N–ZnI2]2, das sich jedoch bei der Kristallisation in [(Me2PhP)3ClIRe≡N–ZnI2 · (OPMe2Ph)] (3) zersetzt. Von den beiden ursprunglich am Re-Atom koordinierten Cl-Atomen wird nur das zum Nitridoliganden cis-standige durch Iod substituiert. 3 bildet monokline Kristalle mit der Raumgruppe P21/n. Die Abstande in der linearen Nitridobrucke (Re–N–Zn = 171,5°) betragen Re–N = 167,9 pm und Zn–N = 204,9 pm. Die Reaktion von [ReNCl2(PMe2Ph)3] mit ZnX2 (X = Cl, I) in THF ergibt die Zweikernkomplexe [(Me2PhP)3Cl2Re≡N–ZnCl2(THF)] (4) und [(Me2PhP)3 · ClIRe≡N–ZnI2(THF)] (5), die isotyp als 4 · THF bzw. 5 · THF in der triklinen Raumgruppe P1 kristallisieren. Die zugehorigen Nitridobrucken weisen folgende Parameter auf: Re–N–Zn = 175,2°, Re–N = 167,7 pm und Zn–N = 202,1 pm fur 4, sowie Re–N–Zn = 174,7°, Re–N = 168,3 pm und Zn–N = 201,2 pm fur 5. Synthesis and Structure of Complexes with Nitrido Bridges between Rhenium and Zinc The reaction of [ReNCl2(PMePh)3] with ZnX2 (X = Cl, Br) in CH2Cl2 yields the tetranuclear complexes [(Me2PhP)3X2Re≡N–ZnX2]2. In case of the reaction with ZnBr2 an exchange of the halogen atoms coordinated to the Re atom occurs. [(Me2PhP)3Cl2Re≡N–ZnCl2]2 (1) crystallizes with one centrosymmetric tetranuclear complex in the triclinic unit cell. [(Me2PhP)3Br2Re≡N–ZnBr2]2 (2) forms triclinic crystals with the composition 2 · 2 CH2Cl2. The centrosymmetric tetranuclear complexes exhibit analogous structures. Two complexes [ReNX2(PMe2Ph)3] coordinate with the terminal nitrido ligands the Zn atoms of a central unit XZn(μ-X)2ZnX. The resulting linear nitrido bridges Re≡N–Zn (Re–N–Zn = 178.4° (1) und 178.0° (2)) are asymmetric with distances Re–N = 170 pm and Zn–N = 199 pm for 1, and Re–N = 167 pm as well as Zn–N = 201 pm for 2. The reaction of [ReNCl2(PMe2Ph)3] with ZnI2 in CH2Cl2 presumably first affords [(Me2PhP)3ClIRe≡N–ZnI2]2, which, however, in the course of crystallization decomposes to yield [(Me2PhP)3ClIRe≡N–ZnI2(OPMe2Ph)] (3). Of the two Cl atoms originally coordinated at the Re atom the one in cis position to the nitrido ligand is substituted by iodine. 3 forms monoclinic crystals with the space group P21/n. The distances in the linear nitrido bridge (Re–N–Zn = 171.5°) are Re–N = 167.9 pm and Zn–N = 204.9 pm. By the reaction of [ReNCl2(PMe2Ph)3] with ZnX2 (X = Cl, I) in THF the dinuclear complexes [(Me2PhP)3Cl2Re≡N–ZnCl2(THF)] (4) and [(Me2PhP)3ClIRe≡N–ZnI2(THF)] (5) are obtained. They crystallize isotypically as 4 · THF or 5 · THF in the triclinic space group P1. Their nitrido bridges have the following parameters: Re–N–Zn = 175.2°, Re–N = 167.7 pm, and Zn–N = 202.1 pm for 4, resp. Re–N–Zn = 174.7°, Re–N = 168.3 pm, and Zn–N = 201.2 pm for 5.

Novel zwitterionic oxorhenium(V) complexes: synthesis, characterization and crystal structure of [ReOX2(Hdhp)(PPh3)] (X = Cl, Br; H2dhp = 2,3-dihydroxypyridine)

Dois novos complexos zwitterionicos de oxorrenio(V), [ReOCl2(Hdhp)(PPh3)] (1) e [ReOBr2(Hdhp)(PPh3)] (2) (H2dhp = 2,3-dihidroxipiridina), foram sintetizados e caracterizados por espectroscopia de absorcao no infravermelho, ressonância magnetica nuclear de 1H e 31P, analise elementar e determinacao da estrutura cristalina e molecular por difracao de raios X em monocristais. Os complexos apresentam geometria de coordenacao octaedrica bastante distorcida, com os dois ligantes haletos arranjados em posicoes cis equatoriais, o ligante trifenilfosfina em posicao trans a um dos haletos e o ligante Hdhp- coordenado de forma bidentada atraves de seus atomos de oxigenio, sendo um em posicao trans ao ligante oxo e o outro em posicao trans com relacao ao outro haleto. Este ligante tem seu atomo de nitrogenio protonado. Os compostos 1 e 2 apresentam empacotamento cristalino bastante diferente, influenciado em ambos os casos por ligacoes de hidrogenio intermoleculares dos tipos N-H...X (X = Cl, Br) e N-H...O.

Synthesis, characterization, and in vitro antiproliferative activity of [salophene]platinum(II) complexes.

A series of methoxy‐ and fluorine‐substituted [salophene]platinum(II) complexes (salophene=N,N′‐bis(salicylidene)‐1,2‐phenylenediamine) were synthesized and characterized by 1H NMR spectroscopy and mass spectrometry. The structure was confirmed on the example of [5‐OCH3‐salophene]platinum(II) (4‐Pt) by crystal structure analysis. The cytotoxicity of all complexes against MCF‐7 cells showed strong dependence on the kind of substituent and its position on the salicylidene moiety, whereas 1‐Pt (H), 3‐Pt (4‐OCH3), and 6‐Pt (3‐F) exhibited high antiproliferative effects (IC50<2 μM). Drug lipophilicity and cellular accumulation were analyzed in an attempt to explain the differences in antitumor potency. To gain insight into their mode of action, DNA interaction studies were performed, in which compounds such as 1‐Pt acted as non‐DNA‐binding platinum anticancer drugs, as neither intercalation nor DNA covalent binding were detected.

[Tc(NBCl2Ph)Cl2(Me2PhP)3] und [Tc(NBH3)Cl2(Me2PhP)3] - die ersten Technetium-Komplexe mit Nitridobrücken zwischen Technetium und Bor

[Tc(NBCl2Ph)Cl2(Me2PhP)3] and [Tc(NBH3)Cl2(Me2PhP)3] – the First Technetium Complexes with Nitrido Bridges between Technetium and Boron [TcNCl2(Me2PhP)3] reacts with BCl2Ph or BH3 · THF at low temperatures under formation of complexes containing a nitrido bridge between technetium and boron. The compounds are instable and decompose at room temperature under cleavage of the N–B bonds. The pale-purple [Tc(NBCl2Ph)Cl2(Me2PhP)3] crystallizes in the orthorhombic space group Fdd2. The Tc≡N bond is only slightly lengthened by the formation of the N–B bond of 1.564(4) A. However, a considerable lengthening of the Tc–Cl bond in trans position to the nitrido ligand is observed which can be attributed to an decreasing of the structural trans influence of the nitrido moiety. A similar structural feature can be found in [Tc(NBH3)Cl2(Me2PhP)3] which is the first structurally characterized transition metal complex containing a nitrido bridge to unsubstituted borane.

Stable gold(iii) complexes with thiosemicarbazone derivativesElectronic supplementary information (ESI) available: Tables S1?4: Hydrogen bonds in the complexes [Au(Hdamp-C1)(L3b)]Cl23H2O, [Au(Hdamp-C1)(L3c)]Cl22H2O, [AuCl(L3a)]Cl2MeOH, [AuCl(L3a)]Cl2MeOH and [AuCl(L3b)]ClMeOH. Fig. S1: Molecular packing scheme in [AuCl(L3a)]Cl2MeOH. See http://www.rsc.org/suppdata/dt/b3/b312978k/

Novel thiosemicarbazonato complexes of gold(III) have been prepared from reactions of [Au(damp-C1,N)Cl2(damp- = 2-(N,N-dimethylaminomethyl)phenyl) or [NBu4][AuCl4] with 2-pyridineformamide thiosemicarbazones (HL). The thiosemicarbazones deprotonate and coordinate as mononegative, tridentate NNS ligands to gold to give [Au(Hdamp-C1)(L)]Cl2 or [AuCl(L)]Cl complexes. The organometallic damp- ligand is protonated during the reactions and the Au-N bond is cleaved. The [AuCl(L)]+ cations represent the first gold(III) complexes with thiourea derivatives which are not stabilised by an additional organometallic ligand. Reactions of [NBu4][AuX4](X = Cl, Br) with diphenylthiocarbazone (dithizone) result in reduction of the metal and the formation of gold(I) complexes of the composition [AuX(SCN4-3,4-Ph2)] where SCN4-3,4-Ph2 is 3,4-diphenyltetrazole thione which is formed from cyclisation of dithizone.