Benzyl-substituted metallocarbene compounds synthesised by our group and others during the past 5 years give a new perspective on their activity as antibiotic and antitumoral drugs. N-heterocyclic carbenes containing an imidazole core were functionalised and their transition metal complexes (M = Ag, Au, Cu, Ru) have shown promising antibacterial as well as anticancer activity in vitro and in vivo. IC50 values in the nanomolar region or antibacterial activity comparable to conventional antibiotics lead the way towards novel drug candidates.

The antimicrobial drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate (SBC3) was evaluated for its ability to function in vivo using larvae of Galleria mellonella. A SBC3 concentration of 25 μg/ml inhibited the growth of Staphylococcus aureus by 71.2 % and Candida albicans by 86.2 % in vitro. Larvae inoculated with 20 μl of SBC3 solution showed no ill effects up to a concentration of 250 μg/ml but administration of 500 μg/ml resulted in a 40 % reduction in larval survival and administration of a dose of 1,000 μg/ml resulted in total larval death at 24 h. Larvae inoculated with S. aureus or C. albicans and subsequently administered SBC3 showed increased survival. Administration of SBC3 to larvae did not boost the insect immune response as indicated by lack of an increase in the density of circulating haemocytes (immune cells). The abundance of a number of proteins involved in the insect immune response was reduced in larvae that received 20 μl SBC3 solution of 100 μg/ml. This is the first demonstration of the in vivo activity of SBC3 against S. aureus and C. albicans and demonstrates that SBC3 does not stimulate a non-specific immune response in larvae.

The anticancer drug candidate 1,3-di(p-methoxybenzyl)-4,5-di(p-isopropylphenyl)-imidazol-2-ylidene cop- per(I) bromide (WBC4) was tested on the NCI 60 cancer cell panel in vitro. WBC4 showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with an average GI50 value of 288 nM. This encouraged maximum tolerable dose (MTD) experiments in mice, where a MTD value of 10 mg/kg was determined with single injec- tions to groups of 2 mice. In the following tumor xenograft experiment WBC4 was given at 5 and 10 mg/kg in 5 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. At the higher dose of 10 mg/kg WBC4 showed borderline toxicity leading to 2 mortalities, while a significant T/C value of 0.38 was observed on day 32. At the lower dose of 5 mg/kg WBC4 induced mild and reversible body weight loss with no toxic deaths. At this dose WBC4 showed an identical significant T/C value of 0.38 on day 32, when compared to the treatment group. Immunohistochemistry for the proliferation marker Ki-67 did not show significant changes due to WBC4 treatment in the animals. However, anti-angiogenic effects by WBC4 treatment were observed in CD31 immuno- histochemistry. Here, significant reduction in microvessel number, area and ratio was determined in tumors treated with 10 mg/kg of WBC4.

The synthesis and characterization of ansa -indenyl zirconocene complexes containing a three carbon atom bridge In addition, their molecular structures have been determined by single crystal X-ray diffraction studies. The catalytic activity of the zirconocene derivatives in the polymerization of ethylene is reported. propanoic acids under these conditions usually give the corresponding 2-aryl-4-chloro-3-for-mylfurans. Single crystal X-ray analysis was successfully performed for 4-[(dimethylamino)-methylene]-2-ferrocenyl-5-oxo-4,5-dihydrofur-an-3-carboxaldehydeand4-[(dimethylamino)- 2 dadtc) 5 ] ) ( 2 ), undergoes sponta- neous oxidation of Co(II) to Co(III), followed by an overall chemical rearrangement, resulting with for- mation of molecular complex 3 . In the [Mo VI (dadtc) 4 ] 6 ) anionofthecomplex 4 ,theMo(VI)centre is located at the fourfold rotoinversion axis and coordinated by eight approximately equidistant sulfur atoms from four bidentate dithiocarbamato ligands in the centre of a slightly distorted triangular dodecahedron. Pt(II) complex 5 , [Pt(H 2 dadtc) 2 ] reveals a distorted square planar coordination of the Pt(II) ion. Complexes were characterised by classical chemical methods and X-ray diffraction studies and tested for their antifungal activities. All complexes revealed encouraging levels of antifungal activity when subjected to the tests of mycelia growth inhibition of Botryosphaeria dothidea . The molecular and supramolecu-lar structures of the complexes are con-trolled by H-bonding ability of the hydrazone ligand. The fluorescence of the ligands are quenched by the Ni 2+

4,5-Di(p-isopropylphenyl)-1H-imidazole (2a) and 4,5-di(p-chlorophenyl)-1H-imidazole (2b) were prepared from the appropriately substituted benzoin precursors and then reacted with five p-substituted benzyl halide derivatives through N-dibenzylation to the symmetrically (3a–j) or through N-monobenzylation followed by N-methylation to the un-symmetrically substituted (5b) imidazolium halides. These halides were further used for the synthesis of the corresponding N-heterocyclic carbene–silver(I) (NHC–silver) acetate complexes 4a–j and 5c. The silver(I) compounds 4b, 4e and 4g were characterised by single crystal X-ray diffraction.

Two series of newly synthesised N-heterocyclic carbene-copper(I) bromide derivatives (1a-e and 2a-e) have been isolated and characterised.A series of highly biologically active symmetrically and un-symmetrically p-benzyl substituted imidazolium halides, reported previously by our group, was chosen as precursors for the series 2a-e.The imidazolium halides were reacted with silver oxide and then transmetallated to copper(I) to yield the corresponding N-heterocyclic carbene (NHC) copper(I) bromide complexes.The NHC-copper(I) bromide complexes 1a-e were found to be cytotoxic, giving IC50 values of 3.8 (+/- 0.9), 7.4 (+/- 2.4), 0.60 (+/- 0.09), 13 (+/- 4) and 42 (+/- 7) mu M, while NHC-copper(I) bromide complexes 2a-e showed IC50 values of 17 (+/- 2), 21 (+/- 3), 26 (+/- 5), 68 (+/- 7) and 61 (+/- 10) mu M against the breast cancer cell line MCF-7, respectively.The same NHC-copper(I) complexes 1a-e exhibited IC50 values of 5.6 (+/- 0.9), 3.3 (+/- 0.6), 0.65 (+/- 0.08), 18 (+/- 3) and 126 (+/- 10) mu M, while NHC-copper(I) bromide complexes 2a-e gave IC50 values of 17 (+/- 2), 19 (+/- 1), 18 (+/- 1), 47 (+/- 3) and 134 (+/- 16) mu M against the renal cancer cell-line Caki-1, respectively. (C) 2013 Elsevier Ltd. All rights reserved.

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 mu M) range between 1 mm and 7 mm for MSSA and 0 mmand 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) mu M, 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) mu M 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) mu M against Caki-1 and 5.8 (+/-0.6) mu M 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 mu M) against Caki-1. (C) 2012 Elsevier B. V. All rights reserved.

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(1) 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-beta-D-glucopyranose (SR) to give the NHC-gold(I)-(2',3',4',6'-tetra-O-acetyl-beta-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) mu M and against MCF-7 of >500, 80 (+/- 15), 19 (+/- 1), 7.1 (+/- 1.2), 2.4 (+/- 0.7), and 7.0 (+/- 1.2) mu M, respectively. IC50 values of 67 (+/- 7), 16 (+/- 2), 41 (+/- 1), 31 (+/- 2), 42 (+/- 5), 18 (+/- 1), 14 (+/- 2), 17 (+/- 2), and 58 (+/- 2) mu M 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) mu M against MCF-7 were found for the Au(I) complexes 7-15.

The promising cytotoxic and anti-angiogenic anticancer drug candidate Titanocene Y, which shows good in vitro and in vivo activity is now studied in connection with its mode of action and transportation by employing spectroscopic methods. The active transportation into the cancer cell via binding to serum albumin was investigated using a competitive displacement titration of the known serum albumin binder 8-anilino-1-naphthalene sulfonic acid in combination with fluorescence spectroscopy. The Gibbs free energy of the system was calculated to analyse the binding degree which was calculated at Delta G = -33 +/- 3 kJ/mol. After confirming the ability of Titanocene Y to bind to serum albumin a number of Titanocene dichloride derivatives were investigated. These derivatives varied in ligand substitution pattern and metal centre from vanadium and iron to silver, and displayed a binding degree range from -24 up to -34 kJ/mol. The difference in the determined value of Gibb's free energy may help to establish the optimal metal and substitution pattern for binding and transportation into target cells. Furthermore, the possible interaction of Titanocene Y with DNA was investigated by UV-Vis and CD spectroscopy. UV-Vis spectroscopy monitored DNA interaction of Titanocene Y via thermal denaturation studies, while Circular Dichroism spectroscopy indicated an interaction between Titanocene Y and the DNA double helix at ambient temperatures. The binding to serum albumin indicates the transport of the metallocene to the cancer cell via protein binding where interaction with DNA may occur.

Symmetrically substituted N-heterocyclic carbene (NHC) precursors 1a–e and 3a–e were synthesised by reacting 4,5-bisaryl-1H-imidazole with 2 equivalents of 4-benzyl bromide, 4-methylbenzyl bromide, 4-methoxybenzyl chloride, 4-methoxycarbonylbenzyl bromide or 4-cyanobenzyl bromide to give the 1,3-bis(p-benzyl substituted)-4,5-bisaryl-imidazolium halides. The NHC-silver(I) acetate complexes (1,3-bisbenzyl-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2a), (1,3-bis(4-methylbenzyl)-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2b), (1,3-bis(4-methoxybenzyl)-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2c), (1,3-bis(4-methoxycarbonylbenzyl)-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2d), (1,3-bis(4-cyanobenzyl)-4,5-bisphenyl-imidazole-2-ylidene) silver(I) acetate (2e), (1,3-bisbenzyl-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4a), (1,3-bis(4-methylbenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4b), (1,3-bis(4-methoxybenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4c), (1,3-bis(4-methoxycarbonylbenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4d) and (1,3-bis(4-cyanobenzyl)-4,5-bis(4-methoxyphenyl)-imidazole-2-ylidene) silver(I) acetate (4e) were yielded by reacting these NHC precursors with silver(I) acetate. The silver(I) acetate complexes 2d, 2e and 4c were characterised by single crystal X-ray diffraction. Qualitative antibacterial studies against the Gram-negative bacteria Escherichia coli and the Gram-positive bacteria Staphylococcus aureus, using the Kirby–Bauer disc diffusion method were carried out on the ten NHC-silver(I) acetate complexes 2a–e and 4a–e. Also the IC50 values of these ten complexes were determined by an MTT-based assay against the human renal cancer cell line Caki-1 and the human breast cancer cell line MCF-7. The complexes 2a–e and 4a–e revealed the following IC50 values in μM against Caki-1: 14 (±1), 3.6 (±1.0), 4.2 (±0.5), 33 (±2), 59 (±4), 21 (±1), 21 (±2), 21 (±1), 34 (±2), 46 (±2) and against MCF-7: 5.8 (±0.6), 3.5 (±0.4), 5.4 (±0.3), 28 (±1), 25 (±2), 11 (±2), 5.0 (±0.3), 6.5 (±0.4), 17 (±1), 13 (±1); respectively.

The synthesis of N-heterocyclic carbene (NHC) silver(I) acetate complexes with varying lipophilic benzyl-substituents at the 1 and 3 positions starting from 4,5-diphenylimidazole, opened a new class of antibiotic drug candidates. These NHC-silver(I) acetate derivatives exhibit interesting structural motifs in the solid state and proved to be soluble and stable in biological media. The leading candidate, SBC3, which was known to exhibit good antibacterial activity in preliminary Kirby-Bauer tests, was tested quantitatively using minimum inhibitory concentrations. NHC-silver(I) acetate complexes were found to have MIC values ranging from 20 to 3.13 μg/mL for a variety of Gram-positive, Gram-negative and mycobacteria tested. These values represent good antibiotic activities against potential pathogens when compared to clinically approved antibiotics. Most striking is the fact that SBC3 is active against methicillin-resistant Staphylococcus aureus with a MIC value of 12.5 μg/mL.

Six new titanocene compounds have been isolated and characterised. These compounds were synthesised from their fulvene precursors using Super Hydride (LiBEt3H) followed by transmetallation with titanium tetrachloride to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((1-methyl-3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5a), bis-[((5-methoxy-1-methyl,3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5b), bis-[((1-methyl,3-diethylaminomethyl)indol-4-yl)methylcyclopentadienyl] titanium (IV) dichloride (5c), bis-[((5-bromo-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5d), bis-[((5-chloro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5e), and bis-[((5-fluoro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5f). All six titanocenes 5a-5f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines using DMSO and Soluphor P as solubilising agents in order to determine their IC50 values. Titanocenes 5a-5f were found to have IC50 values of 10 (±2), 21 (±3), 29 (±4), 140 (±6), and 450 (±10) μM when tested using DMSO.

The anticancer drug candidate (1-methyl-3-(p-cyanobenzyl)benzimidazole-2-ylidene) silver( I) acetate ( SBC1) was tested in vitro against human neuroblastoma cells, UKF-NB-3 and UKF-NB-6, delivering IC50 values of 29 +/- 5 and 29 +/- 4 mu M, while further testing against cisplatin-, carboplatin- and oxaliplatin-resistant UKF-NB-3/6 sub-lines showed no cross-resistance with respect to SBC1. A similar trend was found for SBC1 against the human colon carcinoma cell line HCT8 with an IC50 value of 3.1 +/- 0.9 mu M; SBC1 was again able to break cisplatin- and carboplatin- resistance in the corresponding sub-lines. SBC1 was also tested against the prostate cancer cell line PC-3 and its paclitaxel-resistant sub-line, which gave IC50 values of 14.1 +/- 0.9 and 14.5 +/- 0.8 mu M, which indicated no cross-resistance with paclitaxel. In order to test the possible transport of SBC1 via albumin the binding of SBC1 against this transport protein was measured using a fluorescence titration, which gave an Delta G value of 28 +/- 3 kJ/mol. In circular dichroism and DNA denaturation assays SBC1 proved to be a strongly DNA-binding drug candidate. SBC1 was then given at 25 and 50 mg/kg/d, in four injections to two cohorts of eight CAKI-1 tumor-bearing NMRI:nu/nu mice, while a further cohort was treated with solvent only. At these two dosages SBC1 showed a borderline toxicity leading to mortality and body weight loss, while no significant tumor growth reduction or influence on blood parameter with respect to the solvent-treated control group was observed. Further in vivo testing against zebrafish larvae revealed significant toxicity of SBC1 at micromolar concentrations; no useable anti-angiogenic dosage was observed.

Nonsymmetrically substituted N-heterocyclic carbene (NHC) precursors 1a–d and 3a–d were synthesised by first reacting 1H-(benz)imidazole with p-cyanobenzyl bromide to give 4-(1H-imidazole-1-ylmethyl)benzonitrile (1) and 4-(1H-benzimidazole-1-ylmethyl)benzonitrile (3) and afterwards introducing benzyl bromide, 1-(bromomethyl)-4-methylbenzene, 1-(bromomethyl)-4-methoxybenzene, and methyl 4-(bromomethyl)benzoate. The NHC-silver(I) acetate complexes (1-benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2a), (1-(4-cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2b), (1-(4-cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2c), (1-benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4a), (1-(4-cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4b), (1-(4-cyanobenzyl)-3-(4-methoxybenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4c), and (1-(4-cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4d) were yielded by reacting these NHC precursors with silver(I) acetate. The silver(I) acetate complex 4b was characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial studies against the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli, using the Kirby-Bauer disc diffusion method, were carried out on the seven NHC-silver(I) acetate complexes 2a–c and 4a–d. Also the IC50 values of these seven complexes were determined by an MTT-based assay against the human renal cancer cell line Caki-1. The complexes 2a–c and 4a–c revealed the following IC50 values, respectively, 25 (±1), 15 (±2), 5.4 (±0.8), 16 (±2), 7.1 (±1), 20 (±4), and 14 (±1) μM.

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) mu M.

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 mu m, respectively, on the Caki-1 cell line.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

From the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b), 1H-benzimidazole (1c), 1-methylimidazole (1d), 4,5-dichloro-1-methylimidazole (1e) and 1-methylbenzimidazole (1f) with p-nitrobenzyl bromide (2), symmetrically and non-symmetrically p-nitrobenzyl-substituted N-heterocyclic carbene (NHC) [(3a-f)] precursors were synthesised. These NHC-precursors were then reacted with silver(I) acetate to yield the NHC-silver acetate complexes [1,3-bis(4-nitrobenzyl)imidazol-2-ylidene]silver(I) acetate (4a), [4,5-dichloro-1,3-bis(4-nitrobenzyl)imidazol-2-ylidene] silver(I) acetate (4b), [1,3-bis( 4-nitrobenzyl)benzimidazol-2-ylidene]silver(I) acetate (4c), [1-methyl-3-(4-nitrobenzyl)imidazole-2-ylidene] silver(I) acetate (4d), [4,5-dichloro-1-methyl-3-(4-nitrobenzyl) imidazole-2-ylidene] silver(I) acetate (4e) and [1-methyl-3-(4-nitrobenzyl)benzimidazole-2-ylidene] silver(I) acetate (4f), respectively. The two NHC-silver(I) acetate complexes 4a and 4e were characterised by single-crystal X-ray diffraction. All compounds studied in this work were preliminary screened for their antimicrobial activities in vitro against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative Kirby-Bauer disk-diffusion method. All NHC-silver(I) acetate complexes exhibited medium to high antibacterial activity with areas of clearance ranging from 3 to 7 mm at the highest amount used, whereas the NHC-precursors showed significantly lower activity. In addition, NHC-silver(I) acetate complexes 4a-f had their preliminary cytotoxicity tests on the human renal-cancer cell line Caki-1 and showed medium to high cytotoxicity with IC50 values ranging from 15 (+/-1) to 27 (+/-2) mu M.

The antiproliferative properties and cellular impact of novel substitutionally inert rhodium(III) complexes of the types [Rh{(CH₃)₂ NCS₂}₂(pp)]Cl 3-5 (pp=5,6-Me₂phen, dpq, dppz) and OC-6-23-[Rh(2-S-py)₂(pp)]Cl 6 and 7 (2-S-py=pyridine-2-thiolate; pp=dpq, dppz) have been investigated for the adherent human cancer cell lines MCF-7 and HT-29 and for non-adherent Jurkat cells. Whereas CD and viscosity measurements indicate that the polypyridyl ligands of 4 and 5 intercalate into CT DNA, this is not the case for the analogous pyridine-2-thiolate complexes 6 and 7. Complexes 3-7 all exhibit a high antiproliferative activity towards MCF-7 and HT-29 cells, with IC(50) values in the range 0.055-0.285 μM. As established by online monitoring with a cell-based sensor chip, the highly cytostatic complex 6 (IC(50)=0.059 and 0.078 μM) invokes an immediate concentration-dependent reduction of MCF-7 cell respiration and a time-delayed decrease in cellular impedance, which can be ascribed to the induction of cell death. Annexin V/PI assays demonstrated that 6 also has a pronounced antiproliferative activity towards Jurkat cells and that it invokes extensive apoptosis and high concentrations of reactive oxygen species in these leukemia cells. The observation of a dose-dependent inhibition of the oxygen consumption of isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in this process.