Investigation of Phosphazene Superbase Interactions with [PClN].

In this study, the reaction between phosphazene superbases and a chlorophosphazene trimer ([PClN]) has been investigated. In this room temperature reaction, the phosphazene superbase (MeN)PN(MeN)P═NEt, commonly known as PEt, was shown to behave as a nucleophile, displacing one of the chlorides from [PClN] and producing the tadpole-like structure . The reaction described herein is one of the few instances of a phosphazene superbase behaving as a nucleophile rather than a Brønsted base.

Synthesis, characterization, in vitro SAR study, and preliminary in vivo toxicity evaluation of naphthylmethyl substituted bis-imidazolium salts.

A series of novel bis-imidazolium salts was synthesized, characterized, and evaluated in vitro against a panel of non-small cell lung cancer (NSCLC) cells. Two imidazolium cores were connected with alkyl chains of varying lengths to develop a structure activity relationship (SAR). Increasing the length of the connecting alkyl chain was shown to correlate to an increase in the anti-proliferative activity.

Synthesis and Characterization of Cobalt(II) ,'-Diphenylazodioxide Complexes.

Removal of chloride from CoCl with TlPF in acetonitrile, followed by addition of excess nitrosobenzene, yielded the eight-coordinate cobalt(II) complex salt [Co{Ph(O)NN(O)Ph}](PF), shown by single-crystal X-ray analysis to have a distorted tetragonal geometry. The analogous treatment of the bipyridyl complex Co(bpy)Cl yielded the mixed-ligand cobalt(II) complex salt [Co(bpy){Ph(O)NN(O)Ph}](PF), whose single-crystal X-ray structure displays a trigonal prismatic geometry, similar to that of the iron(II) cation in the previously known complex salt [Fe{Ph(O)NN(O)Ph}](FeCl). The use of TlPF to generate solvated metal complex cations from chloride salts or chlorido complexes, followed by the addition of nitrosobenzene, is shown to be a useful synthetic strategy for the preparation of azodioxide complex cations with the noncoordinating, diamagnetic PF counteranion.

A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

To address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the "drug efficacy metric" (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using an on-target human bronchial epithelial cell-line correlates well (R > 0.

Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N'bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC.

Alkyl- and N,N'-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI-H460, NCI-H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1-4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen.

Synthesis, characterization, and in vitro SAR evaluation of N,N'-bis(arylmethyl)-C-alkyl substituted imidazolium salts.

A series of C-alkyl substituted N,N'-bis(arylmethyl)imidazolium salts were synthesized, characterized, and tested for their in vitro anti-cancer activity against multiple non-small cell lung cancer cell lines by our group and the National Cancer Institute's-60 human tumor cell line screen to establish a structure-activity relationship. Compounds are related to previously published N,N'-bis(arylmethyl)imidazolium salts but utilize the historical quinoline motif and anion effects to increase the aqueous solubility. Multiple derivatives displayed high anti-cancer activity with IC values in the nanomolar to low micromolar range against a panel of non-small cell lung cancer cell lines.

Synthesis, anti-proliferative activity, SAR study, and preliminary in vivo toxicity study of substituted N,N'-bis(arylmethyl)benzimidazolium salts against a panel of non-small cell lung cancer cell lines.

A series of N,N'-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N(N)) and highly lipophilic substituents at the carbon atoms (C and C(C)) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin.

An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor.

Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and (15)N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead.

Group 13 Superacid Adducts of [PCl2N]3.

Irrespective of the order of the addition of reagents, the reactions of [PCl2N]3 with MX3 (MX3 = AlCl3, AlBr3, GaCl3) in the presence of water or gaseous HX give the air- and light-sensitive superacid adducts [PCl2N]3·HMX4. The reactions are quantitative when HX is used. These reactions illustrate a Lewis acid/Brønsted acid dichotomy in which Lewis acid chemistry can become Brønsted acid chemistry in the presence of adventitious water or HX.

Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines.

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin.

Imidazolium salts as small-molecule urinary bladder exfoliants in a murine model.

We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury.

Mercury metallation of the copper protein azurin and structural insight into possible heavy metal reactivity.

Mercury(II) metallation of Pseudomonas aeruginosa azurin has been characterized structurally and biochemically. The X-ray crystal structure at 1.5Å of mercury(II) metallated azurin confirms the coordination of mercury at the copper binding active site and a second surface site.

A binuclear Zn(II)-Zn(II) complex from a 2-hydroxybenzohydrazide-derived Schiff base for selective detection of pyrophosphate.

A hydroxybenzohydrazide-based Schiff base ligand was conveniently synthesized. Upon addition of Zn(2+) cations, the ligand exhibited a high tendency to form a binuclear structure with a 2 : 2 ligand-to-zinc ratio, which was accompanied by a large fluorescence turn-on (λem = 507 nm, ϕfl≈ 0.28).

Structure and conformation of the medium-sized chlorophosphazene rings.

Medium-sized cyclic oligomeric phosphazenes [PCl2N]m (where m = 5-9) that were prepared from the reaction of PCl5 and NH4Cl in refluxing chlorobenzene have been isolated by a combination of sublimation/extraction and column chromatography from the predominant products [PCl2N]3 and [PCl2N]4. The medium-sized rings [PCl2N]m have been characterized by electrospray ionization-mass spectroscopy (ESI-MS), their (31)P chemical shifts have been reassigned, and their T1 relaxation times have been obtained. Crystallographic data has been recollected for [PCl2N]5, and the crystal structures of [PCl2N]6, and [PCl2N]8 are reported.

Isomorphic deactivation of a Pseudomonas aeruginosa oxidoreductase: The crystal structure of Ag(I) metallated azurin at 1.7 Å.

Multiple biophysical methods demonstrate that silver effectively metallates Pseudomonas aeruginosa apo-azurin in solution. X-ray crystallography of the silver-modified protein reveals that silver binds to azurin at the traditional copper mediated active site with nearly identical geometry. Cyclic voltammetry indicates that the silver adduct is redox inert.

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.

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 Interactions between L-tyrosine based nanoparticles decorated with folic acid and cervical cancer cells under physiological flow.

Many anticancer drugs have been established clinically, but their efficacy can be compromised by nonspecific toxicity and an inability to reach the desired cancerous intracellular spaces. In order to address these issues, researchers have explored the use of folic acid as a targeted moiety to increase specificity of chemotherapeutic drugs. To expand upon such research, we have conjugated folic acid to functionalized poly(ethylene glycol) and subsequently decorated the surface of l-tyrosine polyphosphate (LTP) nanoparticles.

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.

A new benzotriazole-mediated stereoflexible gateway to hetero-2,5-diketopiperazines.

Open chain Cbz-L-aa(1)-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5-diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%).

Poly[[{μ(3)-2-[4-(2-hy-droxy-eth-yl)piperazin-1-yl]ethane-sulfonato}-silver(I)] trihydrate].

Ethane-sulfonic acid-based buffers like 2-[4-(2-hy-droxy-eth-yl)-piperazin-1-yl]ethane-sulfonic acid (HEPES) are commonly used in biological experiments because of their ability to act as non-coordinating ligands towards metal ions. However, recent work has shown that some of these buffers may in fact coordinate metal ions. The title complex, {[Ag(C(8)H(17)N(2)O(4)S)]·3H(2)O}(n), is a metal-organic framework formed from HEPES and a silver(I) ion.

Silver metallation of hen egg white lysozyme: X-ray crystal structure and NMR studies.

The X-ray crystal structure, NMR binding studies, and enzyme activity of silver(I) metallated hen egg white lysozyme are presented. Primary bonding of silver is observed through His15 with secondary bonding interactions coming from nearby Arg14 and Asp87. A covalently bound nitrate completes a four coordinate binding pocket.

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.

Group 13 Lewis acid adducts of [PCl2N]3.

Phosphazene polymers are classically synthesized by the high-temperature, ring-opening polymerization (ROP) of [PCl(2)N](3) to give [PCl(2)N](n), followed by functionalization of [PCl(2)N](n) with different side groups. We investigated the interactions of [PCl(2)N](3) with Lewis acids because Lewis acids have been used to induce the high-temperature ROP of [PCl(2)N](3). The reactions of [PCl(2)N](3) with MX(3) (M = group 13, X = halides), under strict anaerobic conditions gave adducts [PCl(2)N](3)·MX(3).

Synthesis and antimicrobial studies of silver N-heterocyclic carbene complexes bearing a methyl benzoate substituent.

Due to the properties of silver as an antimicrobial, our research group has synthesized many different silver carbene complexes. Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized by in situ carbene formation using silver acetate as the base in the reaction. The new compounds were fully characterized by several methods including NMR spectroscopy and X-ray crystallography.