Matthew J. Panzner

The medicinal applications of imidazolium carbene-metal complexes.

Ofele and Wanzlick reported the synthesis of the first N-heterocyclic carbene (NHC) metal complexes in 1968.1,2 The isolation of the first free carbene by Arduengo in 1991 set the scene for an ever-growing interest and advancement in the field of N-heterocyclic carbene chemistry.3 Shortly thereafter, the use of these ligands in organometallic chemistry, particularly in catalysis dramatically increased.4,5 N-heterocyclic carbenes are neutral 2-electron donors, with an ability to bond to both hard and soft metals making them more versatile ligands than phosphines.6 As an added advantage, not only are NHCs easier to synthesize and functionalize than phosphines but they also form a stronger bond to metals and therefore form more stable metal complexes than metal phosphine complexes.7,8 The N-heterocyclic carbene ligands interact with metal centers primarily through strong σ-donation and to a lesser degree through π-backdonation (Figure 1).9,10 Figure 1 Orbital diagram of NHC bonding to metal center. Ghosh and coworkers11,12,13,14,15,16 as well as others17,18,19 took special interest in the exceptional stability of several metal-NHC complexes and conducted in depth analyses in order to gain better insights into the structure and bonding. In particular, the metal-ligand donor-acceptor interactions were inspected using the charge decomposition analysis (CDA). CDA is a tool used to quantitatively estimate the degree of NHC → metal σ-donation, designated by d, and NHC ← metal π-back donation, designated by b.20,21 Thus a higher d/b ratio emphasizes the ability of NHC to function as an effective σ-donor, whereas a lower d/b ratio highlights the greater NHC ← metal π-back donation. Interestingly, in the studies conducted by Ghosh, greater NHC ← metal π-back donation was observed in Pd-NHC complexes exhibiting lower d/b ratios ranging between 2.59 – 3.9913,14 and Au-NHC complexes with d/b ratios ranging between 5.23 – 5.8815,16 as compared to the Ag-NHC complexes with d/b ratios ranging between 7.8 – 12.6811,12,16. This observation could attest to why silver-NHC complexes are particularly better transmetallating agents. The newly emerging interest in the medicinal applications of stable metal NHCs led us to examine the few accounts available in the literature dealing with this area of research. This review will discuss in detail the medicinal applications of various transition metal-NHC complexes including silver, gold, rhodium, ruthenium, and palladium. The antimicrobial, antitumor, and resistance properties, along with proposed mechanisms of action to suppress the bacterial growth or proliferation of tumor cells will be discussed.

Synthesis, Stability, and Antimicrobial Studies of Electronically Tuned Silver Acetate N-Heterocyclic Carbenes

A series of methylated imidazolium salts with varying substituents on the 4 and 5 positions of the imidazole ring were synthesized. These salts were reacted with silver acetate to afford their corresponding silver N-heterocyclic carbene (NHC) complexes. These complexes were then evaluated for their stability in water as well as for their antimicrobial efficacy against a variety of bacterial strains associated with cystic fibrosis and chronic lung infections.

The antimicrobial efficacy of sustained release silver–carbene complex-loaded l-tyrosine polyphosphate nanoparticles: Characterization, in vitro and in vivo studies

The pressing need to treat multi-drug resistant bacteria in the chronically infected lungs of cystic fibrosis (CF) patients has given rise to novel nebulized antimicrobials. We have synthesized a silver-carbene complex (SCC10) active against a variety of bacterial strains associated with CF and chronic lung infections. Our studies have demonstrated that SCC10-loaded into L-tyrosine polyphosphate nanoparticles (LTP NPs) exhibits excellent antimicrobial activity in vitro and in vivo against the CF relevant bacteria Pseudomonas aeruginosa. Encapsulation of SCC10 in LTP NPs provides sustained release of the antimicrobial over the course of several days translating into efficacious results in vivo with only two administered doses over a 72 h period.

In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria

OBJECTIVES Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections. METHODS MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae. RESULTS All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases. CONCLUSIONS The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.

Anticancer Activity of Ag(I) N-Heterocyclic Carbene Complexes Derived from 4,5-Dichloro-1H-Imidazole

A class of Ag(I) N-heterocyclic carbene silver complexes, 1–3, derived from 4,5-dichloro-1H-imidazole has been evaluated for their anticancer activity against the human cancer cell lines OVCAR-3 (ovarian), MB157 (breast), and Hela (cervical). Silver complexes 1–3 are active against the ovarian and breast cancer cell lines. A preliminary in vivo study shows 1 to be active against ovarian cancer in mice. The results obtained in these studies warrant further investigation of these compounds in vivo.

A theobromine derived silver N-heterocyclic carbene: synthesis, characterization, and antimicrobial efficacy studies on cystic fibrosis relevant pathogens

The increasing incidence of multidrug-resistant (MDR) pulmonary infections in the cystic fibrosis (CF) population has prompted the investigation of innovative silver based therapeutics. The functionalization of the naturally occurring xanthine theobromine at the N(1) nitrogen atom with an ethanol substituent followed by the methylation of the N(9) nitrogen atom gives the N-heterocyclic carbene precursor 1-(2-hydroxyethyl)-3,7,9-trimethylxanthinium iodide. The reaction of this xanthinium salt with silver acetate produces the highly hydrophilic silver carbene complex SCC8. The in vitro antimicrobial efficacy of this newly synthesized complex was evaluated with excellent results on a variety of virulent and MDR pathogens isolated from CF patients. A comparative in vivo study between the known caffeine derived silver carbene SCC1 and SCC8 demonstrated the ability of both complexes to improve the survival rates of mice in a pneumonia model utilizing the clinically isolated infectious strain of Pseudomonas aeruginosa PA M57-15.

Synthesis, characterization, and in vivo efficacy of shell cross-linked nanoparticle formulations carrying silver antimicrobials as aerosolized therapeutics.

The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2–4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 ± 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag+ delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence.

Aerosolized Antimicrobial Agents Based on Degradable Dextran Nanoparticles Loaded with Silver Carbene Complexes

Degradable acetalated dextran (Ac-DEX) nanoparticles were prepared and loaded with a hydrophobic silver carbene complex (SCC) by a single-emulsion process. The resulting particles were characterized for morphology and size distribution using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The average particle size and particle size distribution were found to be a function of the ratio of the organic phase to the surfactant containing aqueous phase with a 1:5 volume ratio of Ac-DEX CH(2)Cl(2) (organic):PBS (aqueous) being optimal for the formulation of nanoparticles with an average size of 100 ± 40 nm and a low polydispersity. The SCC loading was found to increase with an increase in the SCC quantity in the initial feed used during particle formulation up to 30% (w/w); however, the encapsulation efficiency was observed to be the best at a feed ratio of 20% (w/w). In vitro efficacy testing of the SCC loaded Ac-DEX nanoparticles demonstrated their activity against both Gram-negative and Gram-positive bacteria; the nanoparticles inhibited the growth of every bacterial species tested. As expected, a higher concentration of drug was required to inhibit bacterial growth when the drug was encapsulated within the nanoparticle formulations compared with the free drug illustrating the desired depot release. Compared with free drug, the Ac-DEX nanoparticles were much more readily suspended in an aqueous phase and subsequently aerosolized, thus providing an effective method of pulmonary drug delivery.

Synthesis, characterization, and antimicrobial activity of silver carbene complexes derived from 4,5,6,7- tetrachlorobenzimidazole against antibiotic resistant bacteria †

Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL(-1). Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.

A fluorescent bis(benzoxazole) ligand: Toward binuclear Zn(II)–Zn(II) assembly

A bis(benzoxazole) ligand (HL) has been synthesized, and its reaction with Zn(OAc)(2) has led to fluorescent complexes via formation of binuclear Zn(II)-Zn(II) cores. The ligand-to-metal ratio of the complexes varies from 1 : 1 to 2 : 1, depending on the reaction conditions. A large binding constant K = 8.3 x 10(20) [M(-3)] has been determined for the reaction L + Zn(2+)-->L(2):Zn(2)(2+). The result indicates that the bis(benzoxazole) ligand is a useful building block to construct a binuclear core. On the basis of X-ray analysis, the binuclear Zn(II)-Zn(II) distance in the complexes is determined to be approximately 3.22 A, which is quite comparable to that found in the enzymes (3.3 A). Absorption and fluorescence study shows that a subtle chemical environmental change within the binuclear core can induce a large optical response.