Combinatorial Materials Science and Catalysis

After forever changing the drug discovery process in the pharmaceutical industry, combinatorial chemistry methodologies are increasingly being applied to the discovery and optimization of more efficient catalysts and materials (see picture). With the advent of new combinatorial synthesis and screening technologies, coupled with integrated data management systems, the application of these technologies to materials science and catalyst research holds tremendous potential and brings high expectations to this new and exciting field.     

C‐phosphorylation of 2,5‐dimethyl‐N‐arylpyrroles

C‐Phosphorylation of 2,5‐dimethylpyrroles with phosphorus (III) halides has been studied. Synthetic methods have been elaborated that provide an access to 3‐phosphorylated 2,5‐dimethylpyrroles, including pyrrole‐substituted halogeno and dihalogeno phosphines; on this basis, a variety of trivalent and pentavalent phosphorus derivatives has been obtained. Ortho‐diphosphorylated 2,5‐dimethyl‐N‐arylpyrrole derivatives have been synthesized for the first time. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10:223–230, 1999     

Induction and stabilization of liquid crystal order in H-bond complexes containing non-mesogenic species

A new approach to create mesomorphic ordered systems is discussed. It is based on the idea to use noncovalent interactions in the designing of thermotropic structures by modelling lyotropic liquid crystal (LC) when the water interlayer is changed by appropriate solid substances that are able to interact with the polar part of an amphiphilic molecule without any strong change in the intermolecular interactions between the non-polar “tails”.     

Reduction of Artifacts in Capacitive Electrocardiogram Signals of Driving Subjects

The development of smart cars with e-health services allows monitoring of the health condition of the driver. Driver comfort is preserved by the use of capacitive electrodes, but the recorded signal is characterized by large artifacts. This paper proposes a method for reducing artifacts from the ECG signal recorded by capacitive electrodes (cECG) in moving subjects. Two dominant artifact types are coarse and slow-changing artifacts. Slow-changing artifacts removal by classical filtering is not feasible as the spectral bands of artifacts and cECG overlap, mostly in the band from 0.5 to 15 Hz. We developed a method for artifact removal, based on estimating the fluctuation around linear trend, for both artifact types, including a condition for determining the presence of coarse artifacts. The method was validated on cECG recorded while driving, with the artifacts predominantly due to the movements, as well as on cECG recorded while lying, where the movements were performed according to a predefined protocol. The proposed method eliminates 96% to 100% of the coarse artifacts, while the slow-changing artifacts are completely reduced for the recorded cECG signals larger than 0.3 V. The obtained results are in accordance with the opinion of medical experts. The method is intended for reliable extraction of cardiovascular parameters to monitor driver fatigue status.     

Oxygen-17 nuclear magnetic resonance spectroscopy of organosulfur compounds. Part III. 17O NMR lanthanide-induced shifts (LIS) of diastereotopic oxygen atoms in trans-2- [alkyl(aryl)sulfonyl]cyclohexanols

The ¹⁷O NMR diastereotopicity or chemical shift differences of diastereotopic sulfonyl oxygens in a series of trans-2-[alkyl(aryl)sulfonyl]cyclohexanols have been determined. From a comparison of their sulfonyl oxygen ¹⁷O NMR lanthanide-induced shifts, equilibrium distributions between diastereomeric sulfonyl oxygen-Eu(fod)₃ complexes were determined and found to be sensitive to both the steric size of the –SO₂R substituent as well as the proximity of the C1 hydroxyl group.     

A new dimerization reaction producing 2‐amino‐9‐oxopyrrolo‐[2,1‐b]quinazoline‐1‐carbonitriles and analogous pyrrolo‐[1,2‐a]thieno[3,2‐d] pyrimidinecar bonitriles

A series of 2‐alkylthio‐4‐oxo‐3‐quinazolineacetonitriles 4 and 2‐alkylthio‐4‐oxothieno[3,2‐d]pyrimidine‐3‐acetonitriles 8 was prepared. Upon treatment with sodium hydride, compounds 4 and 8 react to give 2‐amino‐4,9‐dihydro‐9‐oxopyrrolo[2,1‐b]quinazoline‐1‐carbonitriles 9 and 6‐amino‐4,9‐dihydro‐9‐oxopyrrolo[1,2‐a]thieno[3,2‐d]pyrimidine‐7‐carbonitriles 10 , respectively. The transformation of compounds 4 and 8 to the tricyclic aminonitriles 9 and 10 involves a dimerization step followed by a pyrrole cyclization. The tert‐butyl ester derivatives 4d and 8d upon treatment with sodium hydride underwent a Thorpe‐Ziegler cyclization to provide enaminoesters of fused 1,3‐thiazines ( 16 and 17 , respectively) as major products.     

Structure-based design and in-parallel synthesis of inhibitors of AmpC beta-lactamase.

BACKGROUND: Group I beta-lactamases are a major cause of antibiotic resistance to beta-lactams such as penicillins and cephalosporins. These enzymes are only modestly affected by classic beta-lactam-based inhibitors, such as clavulanic acid. Conversely, small arylboronic acids inhibit these enzymes at sub-micromolar concentrations. Structural studies suggest these inhibitors bind to a well-defined cleft in the group I beta-lactamase AmpC; this cleft binds the ubiquitous R1 side chain of beta-lactams. Intriguingly, much of this cleft is left unoccupied by the small arylboronic acids. RESULTS: To investigate if larger boronic acids might take advantage of this cleft, structure-guided in-parallel synthesis was used to explore new inhibitors of AmpC. Twenty-eight derivatives of the lead compound, 3-aminophenylboronic acid, led to an inhibitor with 80-fold better binding (2; K(i) 83 nM). Molecular docking suggested orientations for this compound in the R1 cleft. Based on the docking results, 12 derivatives of 2 were synthesized, leading to inhibitors with K(i) values of 60 nM and with improved solubility. Several of these inhibitors reversed the resistance of nosocomial Gram-positive bacteria, though they showed little activity against Gram-negative bacteria. The X-ray crystal structure of compound 2 in complex with AmpC was subsequently determined to 2.1 A resolution. The placement of the proximal two-thirds of the inhibitor in the experimental structure corresponds with the docked structure, but a bond rotation leads to a distinctly different placement of the distal part of the inhibitor. In the experimental structure, the inhibitor interacts with conserved residues in the R1 cleft whose role in recognition has not been previously explored. CONCLUSIONS: Combining structure-based design with in-parallel synthesis allowed for the rapid exploration of inhibitor functionality in the R1 cleft of AmpC. The resulting inhibitors differ considerably from beta-lactams but nevertheless inhibit the enzyme well. The crystal structure of 2 (K(i) 83 nM) in complex with AmpC may guide exploration of a highly conserved, largely unexplored cleft, providing a template for further design against AmpC beta-lactamase.     

Active bead-linked immunoassay on protein microarrays

Protein microarrays are becoming a powerful tool in proteome, biochemical, and clinical studies. In addition to the quality of arrayed immobilized probe molecules, sensitivity of the microarray-based assay is highly dependent on the detection technique. Here we suggest four simple techniques for rapid detection of analytes bound to protein microarrays. The techniques employ functionalized magnetic and non-magnetic beads moved to, from, or along the array surface by external forces. In contrast to other labeling techniques actively controlled physical labels: (i) make detection extremely fast to allow microarray reading in seconds; (ii) provide a low background due to active removal of weakly bound beads; and (iii) provide a highly sensitive detection, since one antigen-antibody bond is capable of holding bead immobilized on the array surface. In combination with the electrophoretically assisted active immunoassay we described recently such active reading allows to reduce total indirect immunoassay time to 7-10 min while having sensitivity in the femtomolar concentration range. High speed, sensitivity, and specificity make active bead-linked detection an ideal choice in rapid high-throughput screening and in emergency diagnostics.