David K. Bwambok

Near-Infrared Fluorescent NanoGUMBOS for Biomedical Imaging

Herein, we report on near-infrared (NIR) fluorescent nanoparticles generated from an emergent class of materials we refer to as a Group of Uniform Materials Based on Organic Salts (GUMBOS). GUMBOS are largely frozen ionic liquids, although the concept is more general and is also easily applied to solid ionic materials with melting points in excess of 100 degrees C. Nanoparticles based on GUMBOS (nanoGUMBOS) derived from a NIR fluorophore are prepared using a reprecipitation method and evaluated for in vivo fluorescence imaging. Due to their uniformity, single-step preparation, and composite nature, nanoGUMBOS help to resolve issues with dye leakage problems innate to alternate cellular stains and unlock a myriad of applications for these materials, highlighting exciting possibilities for multifunctional nanoGUMBOS.

Controllable formation of ionic liquid micro- and nanoparticles via a melt-emulsion-quench approach.

We present a facile, scalable, and general method for the size-variable generation of monodispersed, near-spherical solid-state (frozen) ionic liquid nanoparticles based on a novel melt-emulsion-quench approach. Simple manipulation of the internal templating droplets within oil-in-water (o/w) microemulsions also permits the formation of well-defined microspheres. This simple and rapid preparation, requiring neither specialized equipment nor harsh conditions, suggests a wealth of potential for these designer nanomaterials within the biomedical, materials, and analytical communities.

Amino Acid-Based Fluorescent Chiral Ionic Liquid for Enantiomeric Recognition

We report on the synthesis and characterization of a new fluorescent chiral ionic liquid (FCIL), l-phenylalanine ethyl ester bis(trifluoromethane) sulfonimide (l-PheC(2)NTf(2)), capable of serving simultaneously as solvent, chiral selector, and fluorescent reporter in chiral analytical measurements. Enantiomers of different analytes, including fluorescent and nonfluorescent compounds, with a variety of structures were shown to induce wavelength- and analyte-dependent changes in the fluorescence intensity of this FCIL. This system may provide both chemo- and enantioselectivity toward multiple analytes simultaneously. The newly synthesized FCIL, derived from commercially available l-phenylalanine ethyl ester chloride and lithium bis(trifluoromethane) sulfonamide, was obtained as liquid at room temperature and is stable to thermal decomposition up to 270 degrees C. Absorption and fluorescence properties of neat l-PheC(2)NTf(2) were complex. While the absorption properties were similar to phenylalanine with a weakly absorbing tail extending beyond 400 nm, multiple excitation and emission bands were observed in its Excitation-Emission Matrix (EEM). A prominent excimer emission displayed the greatest intensity of all emission bands, and a long-wavelength emission shifted toward the red with increasing excitation wavelength. These different spectral regions were shown to respond differently toward several analytes, including sugars such as glucose and mannose, making this an ideal system to exploit the multidimensional properties of fluorescence. The unique properties of l-PheC(2)NTf(2) combined with EEMs resulted in reliable identification of different enantiomers and measurement of enantiomeric composition. Importantly, the choice of excitation and emission wavelength regions was an important variable shown to improve prediction of enantiomeric composition.

Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro

Hypoxia is a hallmark of solid tumors, including breast cancer, and the extent of tumor hypoxia is associated with treatment resistance and poor prognosis. Considering the limited treatment of hypoxic tumor cells and hence a poor prognosis of breast cancer, the investigation of natural products as potential chemopreventive anti-angiogenic agents is of paramount interest. Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), the primary anthraquinone in the roots of Cassia alata L., is a naturally occurring quinone which exhibits a variety of biologic activities including anti-cancer activity. However, the effect of rhein on endothelial or cancer cells under hypoxic conditions has never been delineated. Therefore, the aim of this study was to investigate whether rhein inhibits angiogenesis and the viability of hormone-dependent (MCF-7) or -independent (MDA-MB-435s) breast cancer cells in vitro under normoxic or hypoxic conditions. Rhein inhibited vascular endothelial growth factor (VEGF(165))-stimulated human umbilical vein endothelial cell (HUVEC) tube formation, proliferation and migration under normoxic and hypoxic conditions. In addition, rhein inhibited in vitro angiogenesis by suppressing the activation of phosphatidylinositol 3-kinase (PI3K), phosphorylated-AKT (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) but showed no inhibitory effects on total AKT or ERK. Rhein dose-dependently inhibited the viability of MCF-7 and MDA-MB-435s breast cancer cells under normoxic or hypoxic conditions, and inhibited cell cycle in both cell lines. Furthermore, Western blotting demonstrated that rhein inhibited heat shock protein 90alpha (Hsp90α) activity to induce degradation of Hsp90 client proteins including nuclear factor-kappa B (NF-κB), COX-2, and HER-2. Rhein also inhibited the expression of hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF(165)), epidermal growth factor (EGF), and the phosphorylation of inhibitor of NF-κB (I-κB) under normoxic or hypoxic conditions. Taken together, these data indicate that rhein is a promising anti-angiogenic compound for breast cancer cell viability and growth. Therefore, further studies including in vivo and pre-clinical need to be performed.

Ephedrinium‐based protic chiral ionic liquids for enantiomeric recognition

We report the synthesis of a series of novel structurally related protic chiral ionic liquids (PCILs) derived from ephedrines. Enantiopure norephedrine, ephedrine, and methylephedrine were neutralized by use of fluorinated acids, bis(trifluoromethanesulfonyl)imide, and bis(pentafluoroethanesulfonyl)imide to afford six PCILs with protonated primary, secondary, and tertiary amines. The goal of this study is to investigate the influence of structure on both chiral recognition abilities and physicochemical properties of these closely related PCILs. The newly synthesized PCILs were characterized by use of nuclear magnetic resonance (NMR), thermal gravimetric analysis, differential scanning calorimetry, circular dichroism (CD), mass spectrometry, and elemental analysis. The PCILs were thermally stable up to 220°C and had glass transition temperatures between -60 and -30°C. Both enantiomers of the PCILs retained chirality throughout the synthesis as demonstrated by use of CD measurements. More interestingly, these ephedrinium PCILs displayed strong chiral recognition capabilities as evidenced by peak splitting of the chemical shift of the trifluoro group of potassium Moshers salt by use of (19)F-NMR. In addition, these PCILs demonstrated enantiomeric recognition capabilities toward a range of structurally diverse analytes using steady-state fluorescence spectroscopy.

Combinatorial Approach to Enantiomeric Discrimination: Synthesis and 19F NMR Screening of a Chiral Ionic Liquid-Modified Silane Library

A parallel library of chiral ionic liquid (CIL)-modified silanes as potential chiral selectors was synthesized, and their enantiomeric discrimination abilities were screened by use of (19)F NMR spectroscopy. The screening method allows for rapid identification of the most enantioselective members of the library and simultaneous investigation of their chiral recognition mechanisms. The library compounds were synthesized using quaternization and anion-exchange reactions. Three major parameters (type of chiral cations, anions, and linker chain lengths) were included and investigated during the synthesis and screening. As expected, the structure of the chiral cation was found to play an important role in determining chiral recognition abilities. In addition, several types of intermolecular interactions including ion-pair, hydrogen bonding, pi-pi stacking, dipole stacking, and steric interactions were found to impact chiral discrimination.

Chiral Ionic Liquids in Chromatographic Separation and Spectroscopic Discrimination

Chiral ionic liquids (CILs) are a subclass of ionic liquids (ILs) in which the cation, anion, or both may be chiral. The chirality can be central, axial, or planar. CILs possess a number of unique advantageous properties which are inherited from ionic liquids including negligible vapor pressure, wide liquidus temperature range, high thermal stability, and high tunability. Due to their dual functionalities as chiral selectors and chiral solvents simultaneously, CILs recently have been widely used both in enantiomeric chromatographic separation and in chiral spectroscopic discrimination. In this chapter, the various applications of CILs in chiral chromatographic separations such as GC, HPLC, CE, and MEKC are reviewed. The applications of CILs in enantiomeric spectroscopic discrimination using techniques such as NMR, fluorescence, and NIR are described. In addition, chiral recognition and separation mechanism using the CILs as chiral selectors or chiral solvents is also discussed.