Inkless microcontact printing on SAMs of Boc- and TBS-protected thiols.

We report a new inkless catalytic muCP technique that achieves accurate, fast, and complete pattern reproduction on SAMs of Boc- and TBS-protected thiols immobilized on gold using a polyurethane-acrylate stamp functionalized with covalently bound sulfonic acids. Pattern transfer is complete at room temperature just after one minute of contact and renders sub-200 nm size structures of chemically differentiated SAMs.

Gold nanoparticles on polarizable surfaces as Raman scattering antennas.

Surface plasmons supported by metal nanoparticles are perturbed by coupling to a surface that is polarizable. Coupling results in enhancement of near fields and may increase the scattering efficiency of radiative modes. In this study, we investigate the Rayleigh and Raman scattering properties of gold nanoparticles functionalized with cyanine deposited on silicon and quartz wafers and on gold thin films. Dark-field scattering images display red shifting of the gold nanoparticle plasmon resonance and doughnut-shaped scattering patterns when particles are deposited on silicon or on a gold film. The imaged radiation patterns and individual particle spectra reveal that the polarizable substrates control both the orientation and brightness of the radiative modes. Comparison with simulation indicates that, in a particle-surface system with a fixed junction width, plasmon band shifts are controlled quantitatively by the permittivity of the wafer or the film. Surface-enhanced resonance Raman scattering (SERRS) spectra and images are collected from cyanine on particles on gold films. SERRS images of the particles on gold films are doughnut-shaped as are their Rayleigh images, indicating that the SERRS is controlled by the polarization of plasmons in the antenna nanostructures. Near-field enhancement and radiative efficiency of the antenna are sufficient to enable Raman scattering cyanines to function as gap field probes. Through collective interpretation of individual particle Rayleigh spectra and spectral simulations, the geometric basis for small observed variations in the wavelength and intensity of plasmon resonant scattering from individual antenna on the three surfaces is explained.

Quantum dot-based theranostics.

Luminescent semiconductor nanocrystals, also known as quantum dots (QDs), have advanced the fields of molecular diagnostics and nanotherapeutics. Much of the initial progress for QDs in biology and medicine has focused on developing new biosensing formats to push the limit of detection sensitivity. Nevertheless, QDs can be more than passive bio-probes or labels for biological imaging and cellular studies. The high surface-to-volume ratio of QDs enables the construction of a "smart" multifunctional nanoplatform, where the QDs serve not only as an imaging agent but also a nanoscaffold catering for therapeutic and diagnostic (theranostic) modalities. This mini review highlights the emerging applications of functionalized QDs as fluorescence contrast agents for imaging or as nanoscale vehicles for delivery of therapeutics, with special attention paid to the promise and challenges towards QD-based theranostics.

Development of Stimulus-Responsive Ligands for the Modulation of Copper and Iron Coordination

The ability to manipulate the coordination chemistry of metal ions has significant ramifications for the study and treatment of metal-related health concerns, including iron overload, UV skin damage, and microbial infection among many other conditions. To address this concern, chelating agents that change their metal binding characteristics in response to external stimuli have been synthesized and characterized by several spectroscopic and chromatographic analytical methods. The primary stimuli of interest for this work are light and hydrogen peroxide.

Herein we report the previously unrecognized photochemistry of aroylhydrazone metal chelator ((E)-N′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) (HAPI) and its relation to HAPI metal binding properties. Based on promising initial results, a series of HAPI analogues was prepared to probe the structure-function relationships of aroylhydrazone photochemistry. These efforts elucidate the tunable nature of several aroylhydrazone photoswitching properties.

Ongoing efforts in this laboratory seek to develop compounds called prochelators that exhibit a switch from low to high metal binding affinity upon activation by a stimulus of interest. In this context, we present new strategies to install multiple desired functions into a single structure. The prochelator 2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (E)-3-(2,4-dihydroxyphenyl)acrylate (PC-HAPI) is masked with a photolabile trans-cinnamic acid protecting group that releases umbelliferone, a UV-absorbing, antioxidant coumarin along with a chelating agent upon UV irradiation. In addition to the antioxidant effects of the coumarin, the released chelator (HAPI) inhibits metal-catalyzed production of damaging reactive oxygen species. Finally a peroxide-sensitive prochelator quinolin-8-yl (Z)-3-(4-hydroxy-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)acrylate (BCQ) has been prepared using a novel synthetic route for functionalized cis-cinnamate esters. BCQ uses a novel masking strategy to trigger a 90-fold increase in fluorescence emission, along with the release of a desired chelator, in the presence of hydrogen peroxide.

In situ chemical modification of peptide microarrays: application to the study of the antibody responses to methylated antigens.

Peptide microarrays are useful tools for characterizing the humoral response against methylated antigens. They are usually prepared by printing unmodified and methylated peptides on substrates such as functionalized microscope glass slides. The preferential capture of antibodies by methylated peptides suggests the specific recognition of methylated epitopes. However, unmodified peptide epitopes can be masked due to their interaction with the substrate. The accessibility of unmodified peptides and thus the specificity of the recognition of methylated peptide epitopes can be probed using the in situ methylation procedure described here. Alternately, the in situ methylation of peptide microarrays allows probing the presence of antibodies directed toward methylated epitopes starting from easy-to-make and cost-effective unmodified peptide libraries. In situ methylation was performed using formaldehyde in the presence of sodium cyanoborohydride and nickel chloride. This chemical procedure converts lysine residues into mono- or dimethyl lysines.

The Unexpected Preference for the fac-Isomer with the Tris(5-ester-substituted-2,2′-bipyridine) Complexes of Ruthenium(II)

The synthesis of a number of new 2,2'-bipyridine ligands, functionalized with bulky ester side groups is reported (L2 - L8). Their reaction with [Ru(DMSO)4Cl2] gives rise to tris-chelate ruthenium(II) metal complexes which show an unusually high proportion of the fac-isomer, as judged by 1H NMR following conversion to the ruthenium(II) complex of 2,2'-bipyridine-5-carboxylic acid methyl ester (L1). The initial reaction appears to have thermodynamic control with the steric bulk of the ligands causing the third ligand to be labile under the reaction conditions used, giving rise to disappointing yields and allowing rearrangement to the more stable facial form. DFT studies indicate that this does not appear to be as a consequence of a metal centered electronic effect. The two isomers of [Ru(L1)3](PF6)2 were separated into the two individual forms using silica preparative plate chromatographic procedures, and the photophysical characteristics of the two forms compared. The results appear to indicate that there is no significant difference in both their room temperature electronic absorption and emission spectra or their excited state lifetimes at 77K.

Influence of plasticizer type and storage conditions on properties of poly(methyl vinyl ether-co-maleic anhydride) bioadhesive films

Poly(methyl vinyl ether-co-maleic anhydride) formed films from aqueous formulations with characteristics that are ideal as a basis for producing a drug-containing bioadhesive delivery system when plasticized with a monohydroxyl functionalized plasticizer. Hence, films containing a novel plasticizer, tripropylene glycol methyl ether (TPME), maintained their adhesive strength and tensile properties when packaged in aluminized foil for extended periods of time. Films plasticized with commonly used polyhydric alcohols, such as the glycerol in this study, underwent an esterification reaction that led to polymer crosslinking, as shown in NMR studies. These revealed the presence of peaks in the ester/carbonyl region, suggesting that glyceride residue formation had been initiated. Given the polyfunctional nature of glycerol, progressive esterification would result in a polyester network and an accompanying profound alteration in the physical characteristics. Indeed, films became brittle over time with a loss of both the aqueous solubility and bioadhesion to porcine skin. In addition, a swelling index was measurable after 7 days, a property not seen with those films containing TPME. This change in bioadhesive strength and pliability was independent of the packaging conditions, rendering the films that contain glycerol as unsuitable as a basis for topical bioadhesive delivery of drug substances. Consequently, films containing TPME have potential as an alternative formulation strategy.

Polymer nanotubes by wetting of ordered porous templates

We have developed a simple technique for the fabrication of polymer nanotubes with a monodisperse size distribution and uniform orientation. When either a polymer melt or solution is placed on a substrate with high surface energy, it will spread to form a thin film, known as a precursor film, similar to the behavior of low molar mass liquids. Similar wetting phenomena occur if porous templates are brought into contact with polymer solutions or melts: A thin surface film will cover the pore walls in the initial stages of wetting. This is because the cohesive driving forces for complete filling are much weaker than the adhesive forces. Wall wetting and complete filling of the pores thus take place on different time scales. The latter is prevented by thermal quenching in the case of melts or by solvent evaporation in the case of solutions, thus preserving a nanotube structure. If the template is of monodisperse size distribution, aligned or ordered, so are the nanotubes, and ordered polymer nanotube arrays can be obtained if the template is removed. Any melt-processible polymer, such as polytetrafluoroethylene (PTFE), blends, or multicomponent solutions can be formed into nanotubes with a wall thickness of a few tens of nanometers. Owing to its versatility, this approach should be a promising route toward functionalized polymer nanotubes.

Detection of Lead Contamination of Water and VOC Contamination of Air Using SOI Micro-Optical Devices

Micro-photonic SOI Mach-Zehnder interferometers were coated with solid-phase micro-extraction materials derived from polydimethylsiloxane to enable sensing of volatile organic compounds of the BTEX class in air. A different coating based on functionalized mesoporous silicates is used to detect lead Pb(II) with a detection limit of <;; 100 ppb in water.

New ionic liquids containing an appended hydroxyl functionality from the atom-efficient, one-pot reaction of 1-methylimidazole and acid with propylene oxide

New ionic liquids containing ( 2- hydroxypropyl)- functionalized imidazolium cations have been synthesized by the atom- efficient, room temperature reaction of 1- methylimidazole with acid and propylene oxide; the acid providing the anionic component of the resultant ionic liquids. The incorporation of the secondary hydroxyl- functionality in the cation causes some interesting modifications to the behavior of these ionic liquids, increasing hydrophilicity and resulting in the unprecedented formation of liquid - liquid biphases with acetone. The single crystal structure of 1-( 2- hydroxypropyl)- 3- methylimidazolium tetraphenylborate, prepared by metathesis of the corresponding chloride- containing ionic liquid, has also been determined.

Long-lived near-infrared luminescent lanthanide complexes of imidodiphosphinate

Near-infrared emitting complexes of Nd(III), Er(III), and Yb(III) based on hexacoordinate lanthanide ions with an aryl functionalized imidodiphosphinate ligand, tpip, have been synthesized and fully characterized. Three tpip ligands form a shell around the lanthanide with the ligand coordinating via the two oxygens leading to neutral complexes, Ln(tpip)(3). In the X-ray crystal structures of Er(III) and Nd(III) complexes there is evidence of CH-pi interactions between the phenyl groups. Photophysical investigations of solution samples of the complexes demonstrate that all complexes exhibit relatively long luminescence lifetimes in nondeuteurated solvents. Luminescence studies of powder samples have also been recorded for examination of the properties of NIR complexes in the solid state for potential material applications. The results underline the effective shielding of the lanthanide by the twelve phenyl groups of the tpip ligands and the reduction of high-energy vibrations in close proximity to the lanthanide, both features important in the design of NIR emitting lanthanide complexes.

Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from L-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)(3)H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from L-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

Non-thiazolidinedione antihyperglycemic agents. 1: Alpha-Heteroatom substituted-beta-phenylpropanoic acids.

A review with 22 refs. The 5-benzylthiazolidine-2,4-dione moiety of insulin sensitizing antidiabetic agents can be replaced by a range of ?-heteroatom functionalized ?-phenylpropanoic acids. ?-Oxy-carboxylic acids show potent antidiabetic activity and one compd., the ?-ethoxyacid (SB 213068), is one of the most potent antihyperglycemic agents yet reported.

Benzylguanidines and Other Galegine Analogues Inducing Weight Loss in Mice

Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing properties when evaluated in BALB/c mice. However, retention of the guanidine and replacement of the dimethylallyl group by a series of functionalized benzyl substituents was shown to exhibit, and in some cases significantly improve, the weight reducing properties of these molecules in BALB/c, ob/ob, and diet induced obesity (DIO) mice models. The lead compound identified, across all models, was 1-(4-chlorobenzyl)guanidine hemisulfate, which gave an average daily weight difference (% from time-matched controls; +/- SEM) of -19.7 +/- 1.0, -11.0 +/- 0.7, and -7.3 +/- 0.8 in BALB/c, ob/ob, and DIO models, respectively.

Controlling Assembly of Mixed Thiol Monolayers on Silver Nanoparticles to Tune Their Surface Properties

Modifying the surfaces of metal nanoparticles with self-assembled monolayers of functionalized thiols provides a simple and direct method to alter their surface properties. Mixed self-assembled monolayers can extend this approach since, in principle, the surfaces can be tuned by altering the proportion of each modifier that is adsorbed. However, this works best if the composition and microstructure of the monolayers can be controlled. Here, we have modified preprepared silver colloids with binary mixtures of thiols at varying concentrations and modifier ratios. Surface-enhanced Raman spectroscopy was then used to determine the effect of altering these parameters on the composition of the resulting mixed monolayers. The data could be explained using a new model based on a modified competitive Langmuir approach. It was found that the composition of the mixed monolayer only reflected the ratio of modifiers in the feedstock when the total amount of modifier was sufficient for approximately one monolayer coverage. At higher modifier concentrations the thermodynamically favored modifier dominated, but working at near monolayer concentrations allowed the surface composition to be controlled by changing the ratios of modifiers. Finally, a positively charged porphyrin probe molecule was used to investigate the microstructure of the mixed monolayers, i.e., homogeneous versus domains. In this case the modifier domains were found to be <2 nm.