Synthesis,Cytotoxicity and Antibacterial Studies of Novel Symmetrically and Nonsymmetrically 4‐(Methoxycarbonyl)benzyl‐Substituted N‐Heterocyclic Carbene–Silver Acetate Complexes

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 anticancer properties of gold(I) and silver(I) N-heterocyclic carbene complexes

Bis(1,3-dimethylimidazol-2-ylidene)silver(I) nitrate and bis(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)silver(I) nitrate were prepared by reacting the corresponding imidazolium nitrate salts with silver oxide. Bis(1,3-dimethylimidazol-2-ylidene)gold(I) nitrate and bis(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)gold(I) nitrate salts were prepared via transmetallation of their silver precursors with chloro dimethylsulfide gold. The anticancer properties were determined using NCI-H460 lung cancer cells. Efficacy was established by comparison of the gold and silver compounds with cisplatin.     

Dinuclear Gold(I) Complexes Bearing N,N′‐Allyl‐Bridged Bisimidazolylidene Ligands

A novel N,N’‐allyl‐bridged bisimidazolium salt and a novel dinuclear Ag(I) and a Au(I) NHC complex are reported. Both metallacyclic complexes have a twisted structural shape due to the rigid allylic system and form two different isomers relating to the position of the double bonds. The allyl‐group shows photoisomerisation, but no reactivity towards bases for the additional coordination of Pd(II).     

Synthesis and Crystal Structure of a Dinuclear Silver(I) Metallocyclophane with N‐Heterocyclic Carbene Linkage

Reaction of the carbene precursor 9,10‐bis(N‐ethylimidazoliummethyl)anthracene hexafluorophosphate ( 1 ) and Ag₂O yielded the dinuclear metallocyclophane ( 2 ) in high yield. The structures of 1 and 2 were determined by X‐ray crystallography.     

The use of thermotropic liquid crystals in organometallic chemistry. Synthesis of new mercury, silver and gold complexes with 4,4′-disubstituted azob

Liquid crystalline 4-XC₆H₄N=NC₆H₄X-4′ [X = C₄H₉ (1a), C_1OH₂₁ (1b), OC₄H₉ (1c), OC₈H₁₇(1d)] can be easily prepared in high yields from the corresponding anilines. In order to study the influence of metals on the thermal properties of these materials, we have obtained adducts [AuCl ₃(4-C₄H₉OC₆H₄N=NC₆H₄OC₄H₉-4′)] (2) and [Ag(OC1O₃)L₂] [L = 4-XC₆H₄N=NC₆H₄X-4′; X = OC₄H, (3a), OC₈H₁₇ (3b)]. The silver adducts show themotropic behaviour. Mercuriation of dialkylazobenzenes 1a-b takes place with [Hg(OAc)₂] and LiCl to give [Hg(R)Cl] [R = C₆H₃(N=NC₆H₄X-4′)-2, X-5; X = C₄H₉ (bpap) (4a), C₁₀H₂₁ (dpap) (4b)] while dialkoxyazobenzenes 1c–d require [Hg (OOCCF₃)₂] to obtain [Hg(R)Cl] [R = C₆H₃(N---NC₆H₄X-4′)-2, X-5; X = OC₄H₉ (bxpap) (4c), OC ₈H₁₇ (4d)]. 4a-c react with NaI to give [HgR₂] [R= bpap (5a), dpap (5b), bxpap (5c), oxpap (5d)l. Both chloroaryl-, 4a and 4c, and diaryl-mercurials, 5a and 5c, act readily as transmetailating agents towards [Me₄N] [AuCl₄] in the presence of [Me₄N]Cl to give [Au(η²-R)Cl₂] [R = bpap (6a), bxpap (6b)]. After reaction of [AuCl ₃(tht)] (tht = tetrahydrothiophene) with [Me₄N]Cl and 4b (1:2:1), [Me₄N][Au(dpap)Cl₃] (7) can be isolated. C---H activati bxpap (8b)]. None of the complexes 4–8 shows mesomorphic behaviour.     

Ferrocenyl‐Coupled N‐Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs

Four gold(I) carbene complexes featuring 4‐ferrocenyl‐substituted imidazol‐2‐ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug‐resistant ones, with low micromolar or nanomolar IC₅₀ (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F‐actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular‐disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.     

Synthesis,Characterization, and in vitro Cytotoxicity of Gold(I) Complexes of 2‐(Diphenylphosphanyl)ethylamine and Dithiocarbamates

Gold(I) complexes of 2‐(diphenylphosphanyl)ethylamine or (2‐aminoethyl)diphenylphosphine (AEP), and dithiocaarbamates (R₂NCS₂) were prepared by the reaction of these ligands with (CH₃)₂S‐AuCl in dichloromethane. The synthesized complexes [Au(AEP)Cl] ( 1 ), [Au(AEP)₂]Cl ( 2 ), and [Au₂(R₂NCS₂)₂]_n (R₂ = dimethyl ( 3 ), diethyl ( 4 ), and dibenzyl ( 5 )) were characterized by elemental analysis, IR, ¹H, ¹³C and ³¹P NMR spectroscopy. The complexes were evaluated for anticancer activity against three cancer cells, A549 (human lung carcinoma), HCT15 (human colon cancer), and MCF7 (human breast cancer) cell lines. Three of the five tested complexes showed significant in vitro cytotoxicity and for A549, the inhibition effect of three compounds is greater than cisplatin.     

Linear Pyrazole‐bridged Tetra(N‐heterocyclic carbene) Ligands and Their Hexanuclear Silver(I) Complexes

New hybrid ligands are reported that combine two types of popular donor groups within a single linear scaffold, viz., a central pyrazolate bridge and two appended bis(N‐heterocyclic carbene) units; the ligand strands thus provide two potentially tridentate {NCC} compartments. The pyrazole/tetraimidazolium proligands, [H₅L¹](PF₆)₄ and [H₅L²](PF₆)₄ , were synthesized via multi‐step protocols, and the NH prototropy of [H₅L¹](PF₆)₄ was examined by variable temperature (VT) NMR spectroscopy, giving solvent dependent activation parameters (ΔH^? = 27.6 kJ · mol^–1, ΔS^? = –125 J · mol^–1 · K^–1 in [D₃]MeCN; ΔH^? = 40.4 kJ · mol^–1, ΔS^? = –86.9 J · mol^–1 · K^–1 in [D₆]DMSO) that are in the range typical for pyrazoles. Reaction of the proligands with Ag₂O gave hexametallic complexes [Ag₆(L¹)₂](PF₆)₄ and [Ag₆(L²)₂](PF₆)₄ that involve all six potential donor atoms of the ligands, viz. the four C^NHC and two N^pz donors, in metal coordination. X‐ray crystallography revealed a chair‐like central {Ag₆} deck in both complexes but different arrangements of the ligand strands, which goes along with significantly different Ag^I ··· Ag^I distances that indicate more pronounced argentophilic interactions in case of [Ag₆(L¹)₂]^{4 +}.     

Syntheses,Structures, and Properties of Phosphorescent Iridium(III) Complexes Containing N‐Heterocyclic Carbene Ligands

The organic salts 1‐(2‐pyridylmethyl)‐3‐alkylbenzimidazolium halide (pm‐RbH ⁺X⁻) and 1‐(2‐pyridylmethyl)‐3‐alkylimidazolium halide (pm‐R′iH ⁺X′⁻) were prepared (where R = 4‐, 3‐, 2‐fluorobenzyl ( 4f , 3f , and 2f , respectively), 4‐, 3‐, 2‐chlorobenzyl ( 4c , 3c , and 2c , respectively); 4‐methoxybenzyl (4mo); 2,3,4,5,6‐pentafluorobenzyl (f₅); benzyl (b); and methyl (m)); X = Cl and Br; R′ = benzyl (b) and methyl (m); and X′ = Cl and I. From these salts, heteroleptic Ir(III ) complexes containing one N ‐heterocyclic carbene (NHC ) ligand [Ir(κ²‐ppy)₂(κ²‐(pm‐Rb))]PF₆ (R = 4f, 1 (PF₆ ); 3f, 2 (PF₆ ); 2f, 3 (PF₆ ); f₅b, 4 (PF₆ ); 4c, 5 (PF₆ ); 3c, 6 (PF₆ ); 2c, 7 (PF₆ ); 4mo, 8 (PF₆ ); b, 9 (PF₆ ); m, 10 (PF₆ )) and [Ir(κ²‐ppy)₂(κ²‐(pm‐R′i))]PF₆ (R = b, 11 (PF₆ ); m, 12 (PF₆ )), were synthesized, and the crystal structures of 1 (PF₆ ), 2 (PF₆ ), 3 (PF₆ ), 5 (PF₆ ), 6 (PF₆ ), 7 (PF₆ ), 9 (PF₆ ), 10 (PF₆ ), and 12 (PF₆ ) were determined by X‐ray diffraction. The neutral NHC ligands 1‐(2‐pyridylmethyl)‐3‐alkylbenzimidazolin‐2‐ylidene (pm‐Rb) and 1‐(2‐pyridylmethyl)‐3‐alkylimidazolin‐2‐ylidene (pm‐R′i) of all cations were found to be involved in the intermolecular π−π stacking interactions with the surrounding cations in the solid state, thereby probably influencing the photophysical behavior in the solid state and in solution. The absorption and emission properties of all the complexes show only small variations.     

Silver–N‐Heterocyclic Carbene Complexes: Synthesis,Characterization, and Antimicrobial Properties

Six new silver complexes containing symmetrical N ‐heterocyclic carbene (NHC ) ligands were synthesized by the reaction of azolium salts with Ag₂O in CH₂Cl₂ . These complexes were tested against Gram‐negative bacterial strains (Escherichia coli and Pseudomonas aeruginosa ), Gram‐positive bacterial strains (Enterococcus faecalis and Staphylococcus aureus ), and fungal strains (Candida albicans and Candida tropicalis ), and all tested complexes showed good activity against the different microorganisms.     

Metallation of Ligands with Biological Activity: Synthesis and X‐ray Characterization of the New Sulfathiazolato Complexes of Gold(I) and Silver(I): [(sulfathiazolato)AuPPh3] and [Ag(sulfathiazolato)]2 (sulfathiazole = N1‐2‐thiazolyl‐sulfanilamide)

Sulfathiazole reacts with [Ph₃PAu(CH₃COO)] in benzene and with Ag(CH₃COO) in methanol giving [(sulfathiazolato)AuPPh₃] ( 1 ) and {[Ag(sulfathiazolato)]₂}_n ( 2 ). While the lattice of 1 contains single molecules with linear N–Au–P bonds, compound 2 performs a polymeric, one‐dimensional assembling of [Ag(sulfathiazolato)]₂ dimers linked through intermolecular Ag···O=S=O interactions along the crystallographic axis b. The silver atoms achieve a tetrahedral configuration through Ag–Ag contacts which measure 2.8427(4) Å, considerably shorter than the normal bonding distance of metallic silver.     

Synthesis and Structural Studies of New (Triphenylphosphine)(trialkoxysilanethiolato)gold(I) Complexes

Compounds of general formula Au{SSi(OR)₃}(PPh₃), R = Prⁱ ( 1 ), Bu^s ( 2 ) or Bu^t ( 3 ), have been obtained by reaction of AuCl(PPh₃) with triethylammonium salts of respective silanethiols, (RO)₃SiSH. Molecular and crystal structures of 1 , 2 , and 3 have been determined by the single crystal X‐ray structural analysis. Compounds 1 and 2 are the first structurally characterized metal derivatives of hydrolytically unstable trialkoxysilanethiols (PrⁱO)₃SiSH and (Bu^sO)₃SiSH.     

Quinobis(imidazolylidene): Synthesis and Study of an Electron‐Configurable Bis(N‐Heterocyclic Carbene) and Its Bimetallic Complexes

Reaction of bromanil with N,N′‐dimesitylformamidine followed by deprotonation with NaN(SiMe₃)₂ afforded 1,1′,3,3′‐tetramesitylquinobis(imidazolylidene) ( 1 ), a bis(N‐heterocyclic carbene) (NHC) with two NHC moieties connected by a redox active p‐quinone residue, in 72 % yield of isolated compound. Bimetallic complexes of 1 were prepared by coupling to FcN₃ ( 2 ) or FcNCS ( 3 ; Fc=ferrocenyl) or coordination to [M(cod)Cl] ( 4 a or 4 b , where M=Rh or Ir, respectively; cod=1,5‐cyclooctadiene). Treatment of 4 a and 4 b with excess CO(g) afforded the corresponding [M(CO)₂Cl] complexes 5 a and 5 b , respectively. Analysis of 2 – 5 by NMR spectroscopy and X‐ray diffraction indicated that the electron‐deficient quinone did not significantly affect the inherent spectral properties or coordination chemistry of the flanking imidazolylidene units, as compared to analogous NHCs. Infrared spectroscopy and cyclic voltammetry revealed that decreasing the electron density at ML_n afforded an increase in the stretching energy and a decrease in the reduction potential of the quinone, indicative of metal–quinone electronic interaction. Differential pulse voltammetry and chronoamperometry of the metal‐centered oxidations in 2 – 4 revealed two single, one‐electron peaks. Thus, the metal atoms bound to 1 are oxidized at indistinguishable potentials and do not appear electronically coupled. However, the metal–quinone interaction was used to increase the electron density at coordinated metal atoms. Infrared spectroelectrochemistry revealed that the average ν_CO values for 5 a and 5 b decreased by 14 and 15 cm^?1, respectively, upon reduction of the quinone embedded within 1 . These shifts correspond to 10 and 12 cm^?1 decreases in the Tolman electronic parameter of this ditopic ligand.     

Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

Metal N‐heterocyclic carbene (NHC) complexes are a promising class of anti‐cancer agents displaying potent in vitro and in vivo activities. Taking a multi‐faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti‐cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti‐tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB‐1, accompanied by expected downstream mechanisms of action. Additionally, Pt^II and Pd^II analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal–NHC scaffold in the design of anti‐cancer metal medicines with multiple molecular targets.     

Tricarbonylrhenium(I) Complexes with N‐Heterocyclic Thiones and Selenols

Reactions of (NEt₄)₂[Re(CO)₃Br₃] with N‐heterocyclic thiols such as 2‐mercaptobenzimidazole (H₂Sbenzim), 2‐mercaptothiazoline (HSthiaz), or 5‐mercapto‐1‐methyltetrazole (HSmetetraz) give rhenium(I) complexes of various compositions: (NEt₄)[Re(CO)₃Br₂(H₂Sbenzim)], [Re(CO)₃(HSthiaz)₃]Br, and (NEt₄)[Re₂(CO)₆(μ‐S‐Smetetraz‐κS)(μ‐N,S‐Smetetraz‐κS,N)₂]. Corresponding reactions with 2‐mercaptopyridine (HSpy) and bis(2‐pyridine)diselenide [(Sepy)₂] did not give defined products in reasonable yields, whereas [Re(CO)₅Br] reacts with HSpy and (Sepy)₂ with formation of [Re(CO)₃(HSpy)₃]Br and [Re₂(CO)₆(Sepy)₂], respectively. All reactions were performed without the addition of a supporting base and the sulfur‐containing organic ligands are coordinated in their thione forms with the exception of Smetetraz^– in its μS‐bridging coordination mode in (NEt₄)[Re₂(CO)₆(μ‐S‐Smetetraz‐κS)(μ‐N,S‐Smetetraz‐κS,N)₂], which can be regarded as thiolate. The bonding mode of the selenium containing ligands in the dimeric compound [Re₂(CO)₆(Sepy)₂] (C–Se distance: 1.93 Å) can also best be described as selenolate. The products are stable on air at an ambient temperature. They were studied spectroscopically and by X‐ray diffraction.