A convergent,scalable and stereoselective synthesis of azole CYP51 inhibitors

The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14α-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV.     

The trigonometric Grassmannian and a difference W-algebra

We introduce a W-algebra which is a central extension of the Lie algebra of difference operators with rational coefficients acting on functions of a discrete variable. We construct its natural fermionic and bosonic representations. We define a module over this difference W-algebra, which characterizes the trigonometric Calogero–Moser spaces.     

Trace formula and Spectral Riemann Surfaces for a class of tri-diagonal matrices

For tri-diagonal matrices arising in the simplified Jaynes–Cummings model, we give an asymptotics of the eigenvalues, prove a trace formula and show that the Spectral Riemann Surface is irreducible.     

Synthesis and photophysical properties of novel amphiphilic ruthenium (II) complexes containing 4,4′‐dialkylaminomethyl‐2,2′‐bipyridyl ligands

The synthesis of a number of new 2,2′‐bipyridine ligands functionalized with bulky amino side groups is reported. Three homoleptic polypyridyl ruthenium (II) complexes, [Ru(L)₃]²⁺ 2(PF₆^?), where L is 4,4′‐dioctylaminomethyl‐2,2′‐bipyridine (Ru4a), 4,4′‐didodecylaminomethyl‐2,2′‐bipyridine (Ru4b) and 4,4′‐dioctadodecylaminomethyl‐2,2′‐bipyridine (Ru4c), have been synthesized. These compounds were characterized and their photophysical properties examined. The electronic spectra of three complexes show pyridyl π → π* transitions in the UV region and metal‐to‐ligand charge transfer bands in the visible region. Copyright © 2005 John Wiley & Sons, Ltd.     

Design parameters for tuning the type 1 Cu multicopper oxidase redox potential: insight from a combination of first principles and empirical molecular dynamics simulations

The redox potentials and reorganization energies of the type 1 (T1) Cu site in four multicopper oxidases were calculated by combining first principles density functional theory (QM) and QM/MM molecular dynamics (MD) simulations. The model enzymes selected included the laccase from Trametes versicolor, the laccase-like enzyme isolated from Bacillus subtilis, CueO required for copper homeostasis in Escherichia coli, and the small laccase (SLAC) from Streptomyces coelicolor. The results demonstrated good agreement with experimental data and provided insight into the parameters that influence the T1 redox potential. Effects of the immediate T1 Cu site environment, including the His(N(δ))-Cys(S)-His(N(δ)) and the axial coordinating amino acid, as well as the proximate H(N)(backbone)-S(Cys) hydrogen bond, were discerned. Furthermore, effects of the protein backbone and side-chains, as well as of the aqueous solvent, were studied by QM/MM molecular dynamics (MD) simulations, providing an understanding of influences beyond the T1 Cu coordination sphere. Suggestions were made regarding an increase of the T1 redox potential in SLAC, i.e., of Met198 and Thr232 in addition to the axial amino acid Met298. Finally, the results of this work presented a framework for understanding parameters that influence the Type 1 Cu MCO redox potential, useful for an ever-growing range of laccase-based applications.     

Conductive macroporous composite chitosan-carbon nanotube scaffolds

Multiwalled carbon nanotubes (MWCNTs) were used as doping material for three-dimensional chitosan scaffolds to develop a highly conductive, porous, and biocompatible composite material. The porous and interconnected structures were formed by the process of thermally induced phase separation followed by freeze-drying applied to an aqueous solution of 1 wt % chitosan acetic acid. The porosity was characterized to be 97% by both mercury intrusion porosimetry measurements and SEM image analysis. When MWCNTs were used as a filler to introduce conductive pathways throughout the chitosan skeleton, the solubilizing hydrophobic and hydrophilic properties of chitosan established stable polymer/MWCNT solutions that yielded a homogeneous distribution of nanotubes throughout the final composite matrix. A percolation theory threshold of approximately 2.5 wt % MWCNTs was determined by measurement of the conductivity as a function of chitosan/MWCNT ratios. The powder resistivity of completely compressed scaffolds also was measured and was found to be similar for all MWCNT concentrations (0.7-0.15 Omega cm powder resistivity for MWCNTs of 0.8-5 wt %) and almost five times lower than the 20 k Omega cm value found for pure chitosan scaffolds.     

Biomimetic synthesis, antibacterial activity and structure-activity properties of the pyroglutamate core of oxazolomycin

Biomimetic intramolecular aldol reactions on oxazolidine templates derived from serine may be used to generate densely functionalised pyroglutamates, which are simpler mimics of the right hand side of oxazolomycin. Some of the compounds from this sequence exhibit in vivo activity against S. aureus and E. coli, suggesting that pyroglutamate scaffolds may be useful templates for the development of novel antibacterials, and cheminformatic analysis has been used to provide some structure-activity data.     

Extracting biological information with computational analysis of Fourier-transform infrared (FTIR) biospectroscopy datasets: current practices to future perspectives

Applying Fourier-transform infrared (FTIR) spectroscopy (or related technologies such as Raman spectroscopy) to biological questions (defined as biospectroscopy) is relatively novel. Potential fields of application include cytological, histological and microbial studies. This potentially provides a rapid and non-destructive approach to clinical diagnosis. Its increase in application is primarily a consequence of developing instrumentation along with computational techniques. In the coming decades, biospectroscopy is likely to become a common tool in the screening or diagnostic laboratory, or even in the general practitioner's clinic. Despite many advances in the biological application of FTIR spectroscopy, there remain challenges in sample preparation, instrumentation and data handling. We focus on the latter, where we identify in the reviewed literature, the existence of four main study goals: Pattern Finding; Biomarker Identification; Imaging; and, Diagnosis. These can be grouped into two frameworks: Exploratory; and, Diagnostic. Existing techniques in Quality Control, Pre-processing, Feature Extraction, Clustering, and Classification are critically reviewed. An aspect that is often visited is that of method choice. Based on the state-of-art, we claim that in the near future research should be focused on the challenges of dataset standardization; building information systems; development and validation of data analysis tools; and, technology transfer. A diagnostic case study using a real-world dataset is presented as an illustration. Many of the methods presented in this review are Machine Learning and Statistical techniques that are extendable to other forms of computer-based biomedical analysis, including mass spectrometry and magnetic resonance.