Synthesis and evaluation of ketophosph(on)ates as beta-lactamase inhibitors

A series of amidoketophosph(on)ates of general structure PhCH2OCONHCH(R)COCHR'(CH2)n(O)P(O2-)(O)R' (R = H, CH3; R' = H, CH3; n = 0, 1; R' = H, CH3, Et, Ph) have been prepared as a potential source of beta-lactamase inhibitors. The phosphonates (n = 0) were obtained by means of the Arbuzov reaction while most of the phosphates were achieved from reaction of phosph(or/on)ic acids with the appropriate diazoketone PhCH2OCONHCH(R)COCR'N2. The electrophilicity of the carbonyl group in the resulting phosph(on)ates was assessed by the degree of hydration in aqueous solution, determined from NMR spectra. These compounds inhibited typical class C and class D beta-lactamases, particularly the latter group, but showed no activity against class A enzymes. To enhance the carbonyl electrophilicity, an alpha-difluorinated analogue (R = H, CHR' = CF2, n = 0, R' = Et) was also prepared, but no enhanced inhibitory activity was observed. All evidence suggested that these compounds inhibited in the carbonyl form rather than by formation of tetrahedral adducts at the beta-lactamase active site. They show promise as leads to specific class D beta-lactamase inhibitors.     

Role of fluctuations in a snug-fit mechanism of KcsA channel selectivity

The thermodynamic exclusion of Na+ relative to K+ in potassium channels is examined by calculating the distribution of binding energies for Na+ and K+ in a model of the selectivity filter of the KcsA potassium channel. These distributions are observed to take a surprisingly simple form: Gaussian with a slight positive skewness that is insignificant in the present context. Complications that might be anticipated from these distributions are not problematic here. Na+ occupies the filter with a mean binding energy substantially lower than that of K+. The difference is comparable to the difference in hydration free energies of Na+ and K+ in bulk aqueous solution. Thus, the average energies of binding to the filter do not discriminate Na+ from K+ when measured from a baseline of the difference in bulk hydration free energies. The strong binding of Na+ constricts the filter, consistent with a negative partial molar volume of Na+ in water in contrast with a positive partial molar volume of K+ in water. Discrimination in favor of K+)can be attributed to the scarcity of favorable binding configurations for Na+ compared to K+. That relative scarcity is quantified as enhanced binding energy fluctuations, which reflects both the energetically stronger binding of Na+ and the constriction of the filter induced by Na+ binding.     

Experimentally measured permanent dipoles induced by hydrogen bonding. The Stark spectrum of indole-NH3

Hydrogen bond pairs involving the chromophore indole have been extensively studied in the gas phase. Here, we report high resolution electronic spectroscopy experiments on the indole-NH(3) hydrogen bond pair in the absence and presence of an electric field. The S(1)-S(0) origin band of this complex recorded in zero field at high resolution reveals two overlapping spectra; a consequence of NH(3) hindered internal rotation. The barrier to internal rotation is predicted by theory to be less than 20 cm(-1) in the ground state, therefore requiring a non-rigid rotor Hamiltonian to interpret the spectra. Conducting the experiment in the presence of an applied electric field further perturbs the already congested spectrum of the complex, but makes possible the measurement of the permanent electric dipole moments in its S(0) and S(1) states. These values reveal significant changes in electron distribution that arise from hydrogen bonding effects.     

Incorporation of ring nitrogens into diphenylamine antioxidants: striking a balance between reactivity and stability

The incorporation of nitrogen atoms into the aryl rings of conventional diphenylamine antioxidants enables the preparation of readily accessible, air-stable analogues, several of which have temperature-independent radical-trapping activities up to 200-fold greater than those of typical commercial diphenylamines. Amazingly, the nitrogen atoms raise the oxidation potentials of the amines without greatly changing their radical-trapping (H-atom transfer) reactivity.     

Ni(HF2)(3-Clpy)4]BF4 (py = pyridine): evidence for spin exchange along strongly distorted F···H···F- bridges in a one-dimensional polymeric chain

[Ni(HF(2))(3-Clpy)(4)]BF(4) (py = pyridine) is a simple one-dimensional (1D) coordination polymer composed of compressed NiN(4)F(2) octahedra that form chains with bridging HF(2)(-) ligands. In spite of significant distortion of the HF(2)(-) bridge, a quasi-1D antiferromagnetic (AFM) behavior was observed with J(FHF) = 4.86 K.     

First-Principles Theory of Muon and Muonium Trapping in the Protein Chain of Cytochrome c and Associated Hyperfine Interactions

The microscopic details of the electron transfer in cytochrome c (cyt c) are being investigated by the Muon Spin Relaxation (μSR) technique. We are using the Hartree–Fock Cluster Procedure to determine the most likely trapping sites for μ⁺ and muonium (Mu) in the protein chain, and have performed extensive calculations in single amino acid molecules of the protein chain of cyt c. The double-bonded oxygen atom of the carboxyl group was identified as the trapping site for both μ⁺ and Mu. Utilizing the wave functions we obtained from the Hartree–Fock calculations, we have determined the hyperfine field that the μ⁺ in Mu experiences while the latter is trapped at the oxygen. This revised version was published online in September 2006 with corrections to the Cover Date.     

Evaluation of fission product isotopes for field or laboratory detection

An International Monitoring System (IMS) is being created to monitor the Comprehensive Nuclear-Test-Ban Treaty (CTBT). Radionuclide aerosols will be monitored to provide positive proof of an atmospheric explosion. In addition, a group of laboratories will perform quality assurance and confirmatory analyses of samples of interest. The field and laboratory systems will perform gamma-ray spectrometric analysis of air filters. While laboratories may undertake additional analysis such as chemical separation and beta counting, the scope of the work reported here is to make evaluations with respect only to gamma-ray spectrometry. Activation products have not been completely considered and are shaded with uncertainty, from the probability of escape from an underground test and the dependence on the sub-surface elemental composition.     

Repolarization studies in amorphous and polycrystalline silicon

A procedure has been developed to extract qualitative and quantitative information on the muonium fractions, in particular the Mu^* fraction, in polycrystalline and amorphous materials from their longitudinal field repolarization curves. Preliminary results for amorphous silicon suggests that both the Mu^* and Mu^* fractions here are generally lower than in crystalline silicon at temperatures below 200K, but the Mu^* fraction may survive to room temperature in this disordered host.