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A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.

Titanium dioxide is a useful material in the biomedical field as it has excellent biocompatibility based on its non-toxicity and non-inflammatory properties. Furthermore, TiO 2 can be excited by UV light to create charge carriers giving rise to photocatalytic redox reactions at the surface and photo-induced super-hydrophilicity. These properties might be exploited for surface decontamination of medical devices and implants. With this in mind, titanium dioxide TiO 2 films were prepared on stainless steel substrates using magnetron sputtering. Silver loaded (Ag–TiO 2 ) films were prepared by the photocatalytic reduction of Ag + from solution. The adsorption of human serum albumin (HSA) was studied. Surface analysis methods used included X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and atomic force microscopy (AFM). The TiO 2 films were predominantly anatase crystal phase and the photoreduced Ag was present at greater than 90% of the silver content as Ag 0 on the surface. Ag loading of the TiO 2 markedly enhanced the Raman signal (ca. 15-fold), but caused significant changes to the spectrum indicating non-specific binding of protein side chain residues to the Ag. The amide I and III modes remained well-resolved and were used to estimate the conformational change induced by the Ag. Raman analysis showed an increase in the intensity of the band at ∼1665 cm −1 assigned to the disordered conformation, suggesting that the adsorption to the Ag sites induces conformational changes in the protein. UVB irradiation of the protein contaminated surfaces caused further changes in the protein conformation, consistent with denaturation and enhanced binding and oxidation, thought to be induced through a photocatalytic mechanism.

Silica shells are grown around colloidally synthesized gold nanorods (AuNRs) to form core–shell particles (AuNR@SiO2) of variable occupancy, defined as the number of AuNRs per silica particle. Multiple AuNR occupancy within the silica shell, confirmed with high-resolution electron microscopy, is reflected in a redshift of the longitudinal plasmon mode of the nanorods due to multipolar coupling between AuNRs of a favored end–end orientation. In addition to the plasmon resonance that dominates their absorbance spectra, FL-AuNR@SiO2, core–shell particles incorporating a lipid probe (rhodamine-DOPE), can be monitored by their fluorescence and Raman signals. Optical and scanning electron microscopy (SEM) images are compared directly, enabling the correlation of spectroscopic characteristics with particle morphology. Raman and SEM images show that the most intense Raman signals come from aggregates of AuNRs trapped within the silica matrix. Biexponential fits to fluorescence decays indicate that competing mechanisms of quenching and fluorescence enhancement contribute to a reduced fluorescence lifetime of rhodamine-DOPE located near the AuNRs.

Two regioselective synthetic routes for 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles of generic formula 1 were developed. These highly efficient and scalable routes circumvent the generally observed poor regioselectivity for the pyrazole alkylation.

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure−activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.

Time resolved spectroscopy has revolutionised our understanding of photochemical and photophysical reactions of inorganic complexes. In this review, we briefly describe the most common time resolved optical spectroscopic methods applied to inorganic complexes and outline some examples and highlights from the recent literature. The review is not intended to be exhaustive, but highlights key recent papers from coordination chemistry, supramolecular chemistry, carbonyl chemistry and bioinorganic chemistry, as well as, recent insights from ultrafast spectroscopy into the photophysics of important prototypes such as [Ru(bpy)3]2+ and [Cu(dmp)2]+. A brief perspective is then presented which discusses areas where time resolved spectroscopy of inorganic complexes could play a particularly important role in the next few years.

Cyanide, a well-known toxic substance that could be used as a weapon of mass destruction, is likely responsible for a substantial percentage of smoke inhalation deaths. The vitamin B12 precursor cobinamide binds cyanide with high affinity, changing color and, correspondingly, its spectrophotometric spectrum in the ultraviolet/visible light range. Based on these spectral changes, we developed a new facile method to measure cyanide in blood using cobinamide. The limit of detection was 0.25 nmol, while the limit of quantitation was ∼0.5 nmol. The method was reliable, requires minimal equipment, and correlated well with a previously established method. Moreover, we adapted it for rapid qualitative assessment of cyanide concentration, which could be used in the field to identify cyanide-poisoned subjects for immediate treatment. © 2010 American Chemical Society.

The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (+/-)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-)-9, from which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-dimethylprolinamides (+)-2 and (-)-2 could be accessed in nearly quantitative yield, without loss of optical purity. The absolute configurations of the resolved prolines and prolinamides were determined by correlation with an intermediate of known absolute stereochemistry.

The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell lymphoma leading to increased trimethylation of histone H3 lysine 27 (H3K27me3). Drug discovery efforts have previously identified a pyridone-based chemical series of EZH2 inhibitors that potently and selectively inhibit EZH2 catalytic activity. These compounds are capable of globally decreasing H3K27me3 levels, de-repressing EZH2 target genes, and inducing growth inhibition of many lymphoma cell lines both in cell culture and in vivo. Through medicinal chemistry optimization, we have developed EZH2 inhibitors with significantly improved potency in both biochemical and cellular assays. These compounds exhibit a prolonged enzyme residence time that can be further extended in vitro through the addition of an H3K27me3 peptide. Herein, we report the biochemical and cellular activity of these new EZH2 inhibitors. Citation Format: Heidi Ott, Glenn van Aller, Jessica Ward, BaoChau Le, Cynthia Rominger, James Foley, Susan Korenchuk, Charles McHugh, Michael Butticello, Charles Blackledge, James Brackley, Joelle Burgess, Celine Duquenne, Neil Johnson, Jiri Kasparec, Louis LaFrance, Mei Li, Kenneth McNulty, Kenneth Newlander, Stuart Romeril, Stanley Schmidt, Mark Schulz, Dai-Shi Su, Dominic Suarez, Xinrong Tian, Christopher Carpenter, Juan Luengo, Ryan Kruger, Steven Knight, Michael T. McCabe. A potent EZH2 inhibitor exhibits long residence time and anti-tumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5379. doi:10.1158/1538-7445.AM2015-5379

We describe the synthesis of gold nanorods (NRs) nucleated by HgTe nanoparticles (NPs) of average size 3 nm in diameter. Growth of ~200 nm by ~50 nm NRs on various surfaces is achieved by using an intermediary polyelectrolyte layer. A poly(dimethyldiallylammonium) chloride (PDDA) monolayer on the surface attracts the thioglycolic acid (TGA) capped HgTe NPs and assists in one-dimensional gold growth. Rod morphology is observed for approximately one third of the resulting features. Confirmation of Au deposition is obtained with x-ray photoelectron spectroscopy and optical absorption measurements that show an increase in the Au plasmon band with time spent in gold growth solution. Au NRs were grown directly on the surface of high quality factor (Q) optical resonators (microspheres and microcylinders). Although the coating procedure reduces the Q of the resonators, whispering gallery modes are sustained. This seeding technique, amenable to many different surfaces, may result in semiconductor-metal nanocomposites with novel electronic and optical properties.