Publications by authors named "Matthew J Panzner"

38 Publications

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

Bioorg Med Chem 2021 Jan 28;30:115893. Epub 2020 Nov 28.

Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA. Electronic address:

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. The National Cancer Institute's NCI-60 human tumor cell line screen confirmed this trend. The compound containing a decyl linker chain, 10, was chosen for further in vivo toxicity studies with C578BL/6 mice. The compound was well tolerated by the mice and all of the animals survived and gained weight over the course of the study.
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http://dx.doi.org/10.1016/j.bmc.2020.115893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903221PMC
January 2021

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

ACS Omega 2018 Nov 27;3(11):16021-16027. Epub 2018 Nov 27.

Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio 44114, United States.

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. Coordination number appears to be more important than electron count in determining the geometry and metal-ligand bond distances of diphenylazodioxide complexes.
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http://dx.doi.org/10.1021/acsomega.8b01200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643636PMC
November 2018

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

Sci Rep 2018 04 23;8(1):6376. Epub 2018 Apr 23.

Department of Microbial Pathogenesis and Immunology, Texas A & M Health Science Center, College Station, TX, 77843, United States.

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 > 0.99) with in vivo efficacy, as measured by median survival hours in a Pseudomonas aeruginosa pneumonia mouse model following aerosolized antimicrobial treatment. In contrast, DEMs derived using off-target primary human dermal fibroblasts correlate poorly (R = 0.0595), which confirms our hypothesis. SCC1 and SCC22 have been identified as promising drug candidates through these studies, and SCC22 demonstrates a dose-dependent survival advantage compared to sham treatment. Finally, silver-bearing biodegradable nanoparticles were predicted to exhibit excellent in vivo efficacy based on its in vitro DEM value, which was confirmed in our mouse pneumonia model. Thus, the DEM successfully predicted the efficacy of various silver-based antimicrobials, and may serve as an excellent tool for the rapid screening of potential antimicrobial candidates without the need for extensive animal experimentation.
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http://dx.doi.org/10.1038/s41598-018-24200-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913254PMC
April 2018

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

Bioorg Med Chem Lett 2017 02 16;27(4):764-775. Epub 2017 Jan 16.

Department of Chemistry, University of Akron, Akron, OH 44325, United States. Electronic address:

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. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1-4 was over 4.4mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.
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http://dx.doi.org/10.1016/j.bmcl.2017.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575737PMC
February 2017

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

Bioorg Med Chem Lett 2017 01 24;27(2):196-202. Epub 2016 Nov 24.

Department of Chemistry, University of Akron, Akron, OH 44325, United States. Electronic address:

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. Several of these derivatives have high aqueous solubilities with potent anti-proliferative properties and are ideal candidates for future in vivo xenograft studies and have high potential to progress into clinic use.
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http://dx.doi.org/10.1016/j.bmcl.2016.11.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204360PMC
January 2017

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.

Bioorg Med Chem 2017 01 5;25(1):421-439. Epub 2016 Nov 5.

Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA. Electronic address:

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. The National Cancer Institute's Developmental Therapeutics Program tested 1, 3-5, 10, 11, 13-18, 20-25, and 28-30 in their 60 human tumor cell line screen. Results were supportive of data observed in our lab. Compounds with hydrophobic substituents have higher anti-cancer activity than compounds with hydrophilic substituents.
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http://dx.doi.org/10.1016/j.bmc.2016.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164943PMC
January 2017

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

Molecules 2016 Jul 16;21(7). Epub 2016 Jul 16.

Department of Chemistry and Biochemistry, The University of Akron, Akron, OH 44325, USA.

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. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins-a heretofore untapped reservoir for antibiotic agents.
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http://dx.doi.org/10.3390/molecules21070846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274284PMC
July 2016

Group 13 Superacid Adducts of [PCl2N]3.

Inorg Chem 2016 Apr 14;55(7):3283-93. Epub 2016 Mar 14.

Department of Chemistry, The University of Akron , Akron, Ohio 44325-3601, United States.

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. The crystal structures of all three [PCl2N]3·HMX4 adducts show that protonation weakens the two P-N bonds that flank the protonated nitrogen atom. Variable-temperature NMR studies indicate that exchange in solution occurs in [PCl2N]3·HMX4, even at lower temperatures than those for [PCl2N]3·MX3. The fragility of [PCl2N]3·HMX4 at or near room temperature and in the presence of light suggests that such adducts are not involved directly as intermediates in the high-temperature ring-opening polymerization (ROP) of [PCl2N]3 to give [PCl2N]n. Attempts to catalyze or initiate the ROP of [PCl2N]3 with the addition of [PCl2N]3·HMX4 at room temperature or at 70 °C were not successful.
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http://dx.doi.org/10.1021/acs.inorgchem.5b02341DOI Listing
April 2016

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

Med Chem Res 2015 Jul 13;24(7):2838-2861. Epub 2015 Feb 13.

Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA.

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. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.
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http://dx.doi.org/10.1007/s00044-015-1330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593509PMC
July 2015

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

Antimicrob Agents Chemother 2015 Sep 29;59(9):5494-502. Epub 2015 Jun 29.

Department of Pediatrics, Washington University, St. Louis, Missouri, USA Department of Molecular Microbiology, Washington University, St. Louis, Missouri, USA

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. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties.
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http://dx.doi.org/10.1128/AAC.00881-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538537PMC
September 2015

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

J Inorg Biochem 2014 Dec 16;141:152-160. Epub 2014 Sep 16.

Department of Chemistry, The University of Akron, Akron, OH 44325, USA. Electronic address:

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. These findings are further validated by NMR, Matrix-assisted laser desorption/ionization spectrometry (MALDI), and UV-visible spectroscopic methods indicating copper displacement from the wild-type protein. Bioinformatic analysis has identified homologous human protein domains computationally, and compared them to the structure of azurin, providing a model for human mercury interactions. Study of the mercury-azurin adduct, in combination with other known examples of protein-heavy metal interactions, could provide further insight into the chemical mechanisms of toxicological interactions, leading toward a global understanding of the biological speciation of toxic heavy metals.
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http://dx.doi.org/10.1016/j.jinorgbio.2014.09.003DOI Listing
December 2014

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

Dalton Trans 2014 Oct 19;43(37):14142-6. Epub 2014 Aug 19.

Department of Chemistry, The University of Akron, Akron, Ohio 44325, USA.

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). The reactivity of the zinc complex was examined using different phosphate anions, which reveals a higher response to acid pyrophosphate anions. Detailed spectroscopic studies show that the pyrophosphate response is based on the ligand displacement mechanism.
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http://dx.doi.org/10.1039/c4dt01799dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161210PMC
October 2014

Structure and conformation of the medium-sized chlorophosphazene rings.

Inorg Chem 2014 Sep 11;53(17):8874-86. Epub 2014 Aug 11.

University of Akron , Department of Chemistry, Akron, Ohio 44325-3601, United States.

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. Halogen-bonding interactions were observed in all the crystal structures of cyclic [PCl2N]m (m = 3-5, 6, 8). The crystal structures of [P(OPh)2N]7 and [P(OPh)2N]8, which are derivatives of the respective [PCl2N]m, are also reported. Comparisons of the intermolecular forces and torsion angles of [PCl2N]8 and [P(OPh)2N]8 with those of three other octameric rings are described. The comparisons show that chlorophosphazenes should not be considered prototypical, in terms of solid-state structure, because of the strong influence of halogen bonding.
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http://dx.doi.org/10.1021/ic500272bDOI Listing
September 2014

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

J Inorg Biochem 2013 Nov 16;128:11-6. Epub 2013 Jul 16.

Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA; Center for Silver Therapeutics Research, The University of Akron, Akron, OH 44325-3601, USA.

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. Our results suggest that a potential mechanism for the microbial toxicity of silver is the deactivation of copper oxidoreductases by the effective binding and structural mimicry by silver without the corresponding function.
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http://dx.doi.org/10.1016/j.jinorgbio.2013.07.011DOI Listing
November 2013

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

ACS Nano 2013 Jun 4;7(6):4977-87. Epub 2013 Jun 4.

Department of Pediatrics, Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

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.
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http://dx.doi.org/10.1021/nn400322fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287418PMC
June 2013

Aerosolized antimicrobial agents based on degradable dextran nanoparticles loaded with silver carbene complexes.

Mol Pharm 2012 Nov 19;9(11):3012-22. Epub 2012 Oct 19.

College of Chemistry, University of California, Berkeley, California 94720-1460, United States.

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.
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http://dx.doi.org/10.1021/mp3004379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579655PMC
November 2012

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

Mol Pharm 2012 Nov 28;9(11):3089-98. Epub 2012 Sep 28.

Department of Biomedical Engineering, The University of Akron, Olson Research Center, Akron, Ohio 44325-0302, United States.

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. These nanoparticles possess the appropriate size (100-500 nm) for internalization as shown by scanning electron microscopy and dynamic light scattering. Under simulated physiological flow, LTP nanoparticles decorated with folic acid (targeted nanoparticles) show a 10-fold greater attachment to HeLa, a cervical cancer cell line, compared to control nanoparticles and to human dermal fibroblasts. The attachment of these targeted nanoparticles progresses at a linear rate, and the strength of this nanoparticle attachment is shown to withstand shear stresses of 3.0 dyn/cm(2). These interactions of the targeted nanoparticles to HeLa are likely a result of a receptor-ligand binding, as a competition study with free folic acid inhibits the nanoparticle attachment. Finally, the targeted nanoparticles encapsulated with a silver based drug show increased efficacy in comparison to nondecorated (plain) nanoparticles and drug alone against HeLa cells. Thus, targeted nanoparticles are a promising delivery platform for developing anticancer therapies that overexpress the folate receptors (FRs).
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http://dx.doi.org/10.1021/mp300221fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518442PMC
November 2012

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

Dalton Trans 2012 Jun 8;41(21):6500-6. Epub 2012 Mar 8.

Center for Silver Therapeutics Research, Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA.

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.
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http://dx.doi.org/10.1039/c2dt00055eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703457PMC
June 2012

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

Chemistry 2012 Feb 13;18(9):2632-8. Epub 2012 Feb 13.

Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA.

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%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results.
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http://dx.doi.org/10.1002/chem.201103143DOI Listing
February 2012

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

Acta Crystallogr Sect E Struct Rep Online 2011 Sep 2;67(Pt 9):m1178-9. Epub 2011 Aug 2.

University of Akron, Department of Chemistry, Akron, OH 44325-3601, USA.

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. In this polymeric complex, each Ag atom is primarily coordinated by two N atoms in a distorted linear geometry. Weaker secondary bonding inter-actions from the hy-droxy and sulfate O atoms of HEPES complete a distorted seesaw geometry. The crystal structure is stabilized by O-H⋯O hydrogen-bonding interactions.
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http://dx.doi.org/10.1107/S160053681103008XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200587PMC
September 2011

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

Chem Commun (Camb) 2011 Dec 31;47(46):12479-81. Epub 2011 Oct 31.

Center for Silver Therapeutics Research, Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA.

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.
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http://dx.doi.org/10.1039/c1cc15908aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677188PMC
December 2011

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

J Antimicrob Chemother 2012 Jan 3;67(1):138-48. Epub 2011 Oct 3.

Department of Biological Sciences, Northern Arizona University, PO Box 5640, Building 21, Flagstaff, AZ 86011, USA.

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.
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http://dx.doi.org/10.1093/jac/dkr408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236053PMC
January 2012

Group 13 Lewis acid adducts of [PCl2N]3.

Inorg Chem 2011 Sep 18;50(18):8937-45. Epub 2011 Aug 18.

Department of Chemistry, The University of Akron, Ohio 44325-3601, USA.

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). Adducts were characterized by X-ray crystallography and multinuclear and variable-temperature NMR studies, and mechanistic understanding of their fluxional behavior in solution was achieved. The properties of the [PCl(2)N](3)·MX(3) adducts at or near room temperature strongly suggests that such adducts are not involved directly as intermediates in the high-temperature ROP of [PCl(2)N](3).
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http://dx.doi.org/10.1021/ic201075zDOI Listing
September 2011

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

Inorganica Chim Acta 2010 Dec;364(1):125-131

The University of Akron, Akron, OH 44325-3601.

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. Preliminary antimicrobial efficacy studies against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli were conducted. The results of this study demonstrated antimicrobial efficacy of the two complexes comparable to silver nitrate, showing their potential for use in the treatment of bacterial infections.
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http://dx.doi.org/10.1016/j.ica.2010.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014616PMC
December 2010

Crown ether complexes of HPCl6.

J Am Chem Soc 2010 Dec 16;132(48):17059-61. Epub 2010 Nov 16.

Department of Chemistry, University of Akron, Akron, Ohio 44325-3601, USA.

The reactions of HCl, PCl5, and a crown ether (12-crown-4 or 18-crown-6) in CHCl3 under anaerobic conditions give complexes of the superacid HPCl6: [H(12-crown-4)][PCl6 ] and [H(18-crown-6)2][PCl6]. The crystal structures indicate that the proton lies roughly in the center of the 12-crown-4 molecule in [H(12-crown-4)][PCl6 ] whereas it lies between two oxygen atoms of two different 18-crown-6 molecules in [H(18-crown-6)2][PCl6].
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http://dx.doi.org/10.1021/ja1064697DOI Listing
December 2010

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

Dalton Trans 2009 Sep 6(35):7308-13. Epub 2009 Aug 6.

Department of Chemistry, The University of Akron, Akron, OH 44325-3601, USA.

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.
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http://dx.doi.org/10.1039/b907726jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867067PMC
September 2009

A fluorescent bis(benzoxazole) ligand: toward binuclear Zn(II)-Zn(II) assembly.

Dalton Trans 2010 Jun 4;39(22):5254-9. Epub 2010 May 4.

Department of Chemistry & Maurice Morton Institute of Polymer Science, The University of Akron, Akron, OH 44325, USA.

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.
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http://dx.doi.org/10.1039/c000989jDOI Listing
June 2010

Host-guest assembly of squaraine dye in cucurbit[8]uril: its implication in fluorescent probe for mercury ions.

Chem Commun (Camb) 2010 Jun 20;46(23):4073-5. Epub 2010 Apr 20.

Department of Chemistry & Maurice Morton Institute of Polymer Science, The University of Akron, Akron, OH 44325, USA.

The binding interactions between SQ2 squaraine dye and cucurbit[8]uril (CB8) effectively removes the aggregation of SQ2 in aqueous solution by forming a 1 : 1 inclusion complex. The resulting SQ2.CB8 complex exhibits highly selective fluorescence quenching by Hg(2+) ions, as a result of the synergetic binding between CB8, SQ2 and metal cation.
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http://dx.doi.org/10.1039/c002219pDOI Listing
June 2010

Synthesis and in vitro Efficacy Studies of Silver Carbene Complexes on Biosafety Level 3 Bacteria.

Eur J Inorg Chem 2009 May;2009(13):1739-1745

Department of Chemistry, University of Akron, Akron, OH 44325-3601, USA.

A series of N-heterocyclic carbene silver complexes have been synthesized and tested against the select group of bio-safety level 3 bacteria Burkholderia pseudomallei, Burkholderia mallei, Bacillus anthracis, methicillin-resistant Staphylococcus aureus and Yersinia pestis. Minimal inhibitory concentrations, minimal bactericidal and killing assays demonstrated the exceptional efficacy of the complexes against these potentially weaponizable pathogens.
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http://dx.doi.org/10.1002/ejic.200801159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755586PMC
May 2009

The medicinal applications of imidazolium carbene-metal complexes.

Chem Rev 2009 Aug;109(8):3859-84

Department of Chemistry, The University of Akron, Akron, Ohio 44325-3601, USA.

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http://dx.doi.org/10.1021/cr800500uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763352PMC
August 2009