Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D-Ala-D-Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64?mg/L to 2 and 1–2?mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC₅₀ value of 1i against VIM-2 was 9.8 and 2.2?μM after 5 and 20?min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120?μM.     

Simulations of the PHOS detector in the ALICE experiment at CERN

In 2005 the ALICE experiment will start at the Large Hadron Collider at CERN. It will investigate hot and dense strongly interacting matter formed in heavy ion collisions. The photon spectrometer of the ALICE detector will be designed to identify direct photons. To optimize the detector, simulations will be carried out.     

New amine-templated zinc phosphates with a temperature-induced increase of structural dimensionality

Three new amine-templated zinc phosphates, [C4N2H14][Zn(HPO4)2].H2O, AU-I, [C4N2H14][Zn2(H(0.5)PO4)2(H2PO4)], AU-II, and [C4N2H14][Zn5(H2O)(PO4)4], AU-III, are prepared by hydrothermal synthesis using an organic amine, N,N'-dimethylethylendiamine CH3NHCH2CH2NHCH3, as structure-directing agent. The three materials are prepared from the same reaction mixture, 1Zn(CH3CO2)2:3.05H3PO4:2.25CH3NHCH2CH2NHCH3:138H2O (pH = 5.1), AU-I at RT, AU-II at 60 degrees C, and AU-III at 170 degrees C. The materials are built from corner-sharing ZnO4 and PO4 tetrahedra forming chains, layers, or framework structures for AU-I to III, respectively, and are linked together by hydrogen bonds via the diprotonated amine ions. The complete hydrogen-bond scheme is resolved for these new compounds and reveals some interesting phenomena, for example, a hydrogen shared between two phosphate groups in AU-II, thereby forming H(0.5)PO4 groups. Furthermore, the water molecules are different; that is, in AU-I they act as hydrogen-bond donor and acceptor, whereas they act as ligand in AU-III with coordination to Zn. The structures of the compounds are determined by single-crystal X-ray diffraction analysis. AU-I, [C4N2H14][Zn(HPO4)2].H2O, crystallizes in the triclinic space group P-1, a = 8.215(2), b = 8.810(3), c = 8.861(3) A, alpha = 88.001(4) degrees , beta = 89.818(5) degrees , and gamma = 89.773(5) degrees , Z = 2. AU-II, [C4N2H14][Zn2(H(0.5)PO4)2(H2PO4)], is monoclinic, P2/n, a = 11.7877(4), b = 5.2093(2), c = 12.2031(4) A, beta = 98.198(1) degrees , Z = 2. AU-III, [C4N2H14][Zn5(H2O)(PO4)4], crystallizes in the orthorhombic space group Pna2(1) with lattice parameters, a = 20.723(2), b = 5.2095(6), c = 17.874(2) A, Z = 4. The phase stability investigated by systematic hydrothermal synthesis is presented, and the materials are further characterized by 31P solid-state MAS NMR, for example, by determination of 31P chemical shift anisotropies for AU-III, while the thermal behavior is investigated by thermogravimetry (TG).     

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.     

Electronic structure of high-valent transition metal corrolazine complexes. The young and innocent?

This is a first quantum chemical study of corrolazine complexes. DFT calculations suggest that despite their extremely contracted central cavities, compared with porphyrins, a variety of corrolazine complexes may be expected to exist as stable compounds. The calculations also indicate that corrolazine complexes may be regarded as strongly electron-deficient analogues of corrole complexes. Thus, the calculated valence ionization potentials of P(V) and Cu(III) corrolazine derivatives are dramatically higher than those of analogous corrole derivatives. In addition, DFT calculations on Fe(IV) and Mn(IV) corrole and corrolazine derivatives suggest that compared with the often noninnocent corrole ligands, corrolazines are electronically more innocent and stabilize "purer" high-valent states of transition metal ions.     

New rubidium zinc hydrogen phosphate,Rb2Zn2(HPO4)3: synthesis,crystal structure,and 31P single-crystal NMR

A new rubidium zinc hydrogen phosphate, Rb2Zn2(HPO4)3, is prepared by an unusual method utilizing long nucleation times. This material is crystallized from a gel with an initial composition of 1.0 ZnO/0.94 P2O5/0.96 Rb2O/0.04 Li2O/41 H2O, while the phosphate concentration equals 1.6 M and pH = 3.5. The gel is placed in a sealed Pyrex flask at 52 degrees C, and after 4.5 months crystallization of Rb2Zn2(HPO4)3 is noticed. This new crystalline compound has a three-dimensional framework structure built from spiral chains of alternating PO4 and ZnO4 tetrahedra connected pairwise and assembled by other PO4 tetrahedra, rubidium ions, and hydrogen bonds. The two rubidium ions, Rb(1) and Rb(2), have an exceptionally low number of oxygen contacts in the first coordination sphere, five and seven, respectively. Crystal data: monoclinic, P2(1)/c (no. 14), a = 12.5880(4), b = 12.7170(8), c = 7.5827(8) A, beta = 96.100(1) degrees, Z = 4. A single-crystal 31P NMR investigation of Rb2Zn2(HPO4)3 was performed employing a two-axis goniometer probe and reveals the presence of three chemically and six magnetically nonequivalent phosphorus sites, in accordance with the crystal structure. 31P chemical shielding anisotropies and isotropic chemical shifts (-3.3(3), -2.6(3), and 2.0(3) ppm) have been determined for the three phosphorus sites.     

Determination of homogeneity of standard materials by ion microscopy

Summary Secondary-ion microanalysis is used to investigate the homogeneity (at the microlevel) of a number of standard reference materials. High mass-resolution measurements are accomplished with a CAMECA IMS-300 ion microscope/ion microprobe equipped with an electrostatic analyser. By use of a 5.5-keV¹⁶O₂ ⁺ primary ion beam with approximately 1A intensity the following materials were investigated: NBS-SRM copper-base alloys, low-alloy steels and zinc-base alloys, and Aluminium Péchiney Al-Si-Cu, Al-Cu and Al-Mn alloys. The sampling-constant concept was applied in order to evaluate the applicability of the reference materials for micro-probe analysis, and other microanalytical techniques. The degree of heterogeneity was estimated and the number of replicate analyses required for achieving 5 and 10% precision were calculated. The results show that care must be taken when using these standards for calibration work in SIMS and other microsampling techniques, since heterogeneity on the microscale is proven for a number of elements. The technique was also applied to the determination of the homogeneity of standard samples of boron in zirconium metal from the Bureau of Reference Materials of the EEC.

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Bestimmung der Homogenität von Standardproben durch Ionenmikroskopie

Zusammenfassung Sekundärionenmikroanalyse wurde zur Untersuchung der Homogenität einiger Standardreferenzmaterialien im Mikrobereich verwendet, wobei Messungen mit hoher Massenauflösung mittels einer CAMECA IMS-300 Ionenmikroskop/Ionenmikrosonde durchgeführt wurden, die mit einem elektrostatischen Sektor ausgestattet ist. Nachstehende Materialien wurden unter Verwendung eines 5,5 keV¹⁶O₂ ⁺-Primärionenstrahls mit etwa 1A Intensität untersucht: NBS-SRM Kupferlegierungen, NBS-SRM niedrig legierte Stähle, NBS-SRM Zinklegierungen und Aluminium Péchiney Al-Si-Cu-, Al-Cu- und Al-Mn-Legierungen.Zur Überprüfung der Verwendbarkeit der Referenzmaterialien für Mikrosondenanalysen und andere mikroanalytische Methoden wurde das Sampling-Constant-Konzept angewandt. Nach dem Abschätzen des He-terogenitätsgrades wird die Anzahl der Wiederholungen von Analysen berechnet, die für 5 und 10% Genauigkeit notwendig sind. Da Heterogenität im Mikrobereich für mehrere Elemente erwiesen ist, weisen die Resultate auf die anzuwendende Sorgfalt, soferne diese Standards für Eichungen in SIMS und anderen mikroanalytischen Methoden Verwendung finden sollen. Ebenso wird diese Technik für die Bestimmung der Homogenität von Bor in Standardproben des Bureau of Reference Materials des E. E. C. angewandt.

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Presented at the 8th International Microchemical Symposium, Graz, August 25–30, 1980.     

Image processing in secondary ion mass spectrometry

The application of image processing in secondary ion mass spectrometry is discussed. The Cameca 4f SIMS uses a single microchannel plate and a highly sensitive camera in combination with an image processor with real time capabilities (Kontron IBAS). An automation procedure with image integration, extended dynamic range image acquisition and retro depth profiling is presented and illustrated with practical applications.     

Thermo-mechanical characterisation of in-plane properties for CSM E-glass epoxy polymer composite materials – Part 2: Young's modulus

The in-plane Young's modulus of a CSM E-glass/epoxy material is characterised through the use of dynamic mechanical analysis (DMA). The measured data is used to generate material models which describe the property behaviour as a function of conversion and temperature. Gelation of the epoxy resin plays a major role in the modulus development and is measured directly on the glass/epoxy material. The Young's modulus is described through a bi-functional model including the liquid/solid transition of the material. The evolution of Young's modulus is modelled by decoupling modulus increments caused by time and temperature, and is graphically illustrated through a Modulus-Temperature-Transformation (MTT) diagram. Based on the established material models presented in this paper and models in Part-1, it is feasible to assess residual stresses and shape distortions of composite parts made from this glass/epoxy material.     

Stress‐Induced Domain Wall Motion in a Ferroelastic Mn3+ Spin Crossover Complex

Domain wall motion is detected for the first time during the transition to a ferroelastic and spin state ordered phase of a spin crossover complex. Single‐crystal X‐ray diffraction and resonant ultrasound spectroscopy (RUS) revealed two distinct symmetry‐breaking phase transitions in the mononuclear Mn³⁺ compound [Mn(3,5‐diBr‐sal₂(323))]BPh₄, 1. The first at 250 K, involves the space group change Cc→Pc and is thermodynamically continuous, while the second, Pc→P1 at 85 K, is discontinuous and related to spin crossover and spin state ordering. Stress‐induced domain wall mobility was interpreted on the basis of a steep increase in acoustic loss immediately below the the Pc‐P1 transition