High-volume cellular screening for anticancer agents with combinatorial chemical libraries: A new methodology

Summary A single-step cancer cell cytotoxic assay system for anticancer drug discovery has been developed which facilitates rapid screening of large combinatorial chemical libraries synthesized using the one-bead-one-compound (OBOC) methodology. Each OBOC library bead incorporates two orthogonally cleavable linkers that release the bead-bound compound at a different pH. The assay utilizes high concentrations of tumor cells mixed directly with OBOC beads and plated in soft agarose containing tissue culture medium. One of the orthogonal linkers is cleaved at neutral pH in tissue culture releasing an aliquot of compound to diffuse at a relatively high local concentration into the soft agarose immediately surrounding the bead. Active compounds are identified visually from a clear ring of tumor cell lysis which forms within 48 h around just the rare bead releasing a cytotoxic compound. The bead releasing a cytotoxin is then plucked from the agar and the remaining compound still linked to the bead can be released for structural analysis, followed by compound resynthesis and confirmatory testing. This assay system has been successfully applied to identification of lead cytotoxic compounds from model peptidic and non-peptidic combinatorial chemical libraries. Use of this methodology may facilitate anticancer drug discovery.     

Complexes of a Zn‐metalloenzyme binding site with hydroxamate‐containing ligands. A case for detailed benchmarkings of polarizable molecular mechanics/dynamics potentials when the experimental binding structure is unknown

Zn‐metalloproteins are a major class of targets for drug design. They constitute a demanding testing ground for polarizable molecular mechanics/dynamics aimed at extending the realm of quantum chemistry (QC) to very long‐duration molecular dynamics (MD). The reliability of such procedures needs to be demonstrated upon comparing the relative stabilities of competing candidate complexes of inhibitors with the recognition site stabilized in the course of MD. This could be necessary when no information is available regarding the experimental structure of the inhibitor–protein complex. Thus, this study bears on the phosphomannose isomerase (PMI) enzyme, considered as a potential therapeutic target for the treatment of several bacterial and parasitic diseases. We consider its complexes with 5‐phospho‐d ‐arabinonohydroxamate and three analog ligands differing by the number and location of their hydroxyl groups. We evaluate the energy accuracy expectable from a polarizable molecular mechanics procedure, SIBFA. This is done by comparisons with ab initio quantum‐chemistry (QC) calculations in the following cases: (a) the complexes of the four ligands in three distinct structures extracted from the entire PMI‐ligand energy‐minimized structures, and totaling up to 264 atoms; (b) the solvation energies of several energy‐minimized complexes of each ligand with a shell of 64 water molecules; (c) the conformational energy differences of each ligand in different conformations characterized in the course of energy‐minimizations; and (d) the continuum solvation energies of the ligands in different conformations. The agreements with the QC results appear convincing. On these bases, we discuss the prospects of applying the procedure to ligand‐macromolecule recognition problems. © 2016 Wiley Periodicals, Inc.     

Single-laser-shot-induced complete bidirectional spin transition at room temperature in single crystals of (FeII(pyrazine)(Pt(CN)4))

Single crystals of the {Fe (II)(pyrazine)[Pt(CN) 4]} spin crossover complex were synthesized by a slow diffusion method. The crystals exhibit a thermal spin transition around room temperature (298 K), which is accompanied by a 14 K wide hysteresis loop. X-ray single-crystal analysis confirms that this compound crystallizes in the tetragonal P4/ mmm space group in both spin states. Within the thermal hysteresis region a complete bidirectional photoconversion was induced between the two phases (high spin right arrow over left arrow low spin) when a short single laser pulse (4 ns, 532 nm) was shined on the sample.     

Metal-to-ligand and ligand-to-metal charge transfer in thin films of Prussian blue analogues investigated by X-ray absorption spectroscopy

A series of thin films of Prussian blue analogues is investigated by X-ray absorption spectroscopy (XAS) at the Fe, Co and Mn L(2,3)-edges. The ligand field multiplet theory enables us to examine accurately the electronic structure of these materials. Experimental XAS spectra of CoFe Prussian blue analogues are successfully reproduced using a ground state configuration including metal-to-ligand (MLCT) and ligand-to-metal charge transfer (LMCT) at the Co and Fe L(2,3)-edges. In particular, a huge improvement is achieved for satellite peaks at the Co(iii) L(2,3)-edges compared to previous calculations in the literature based on LMCT effects only. On the other hand, XAS spectra of MnFe analogues synthesized for the first time, can be reproduced conveniently by taking into account either MLCT or LMCT depending on the conditions of the sample preparation. For each thin film, the proportion of the different oxidation states of Co, Fe and Mn is evaluated. Unexpectedly, this analysis reveals the presence of a significant amount of a reduced phase, which turns out to be strongly dependent on the sample synthesis and storage conditions.     

Laser-induced breakdown spectroscopy of carbon in helium and nitrogen at high pressure

This work is devoted to the study of the gas pressure effect on the laser-induced breakdown spectroscopy signal intensity of carbon. Experiments are performed, using a 1064 nm Nd:YAG laser, with carbon solid samples placed inside a high pressure chamber filled with helium or nitrogen, the gas pressure varying from 1 to 80 atm. The signal intensity of the carbon line (247.86 nm) decreases with increasing pressure. As the plasma size strongly decreases with pressure, two collection optical setups are used, showing different raw results. To take into account the plasma size evolution with pressure, calculated corrections are applied to the collected light intensity. Carbon line emission is measured and corrected as a function of pressure in both gases. At 1 atm, the emission line is found to be greater in helium than in nitrogen by a factor of approximately 3, whereas the intensities in the two gases become close to each other at 80 atm.     

Ferromagnetic phases due to competing short- and long-range interactions in the spin-5/2 and spin-2 Blume–Capel model

We broaden the study of the statistical physics of the spin-S Blume–Capel model with ferromagnetic mean-field interactions J in competition with short-range antiferromagnetic interactions K in a linear chain in the thermodynamic limit. This work is dedicated to the case when S takes the half-integer spin $S=5/2$ and when S assumes the integer value $S=2$. In both cases the phase diagrams exhibit new ferromagnetic phases (for certain values of K) enclosed by branches emerging from the first-order frontiers of the pure ferromagnetic model. For finite temperatures the complex topologies were obtained by numerical minimization of the free energy and some results were confirmed by Monte Carlo simulations.     

A bis­(acetyl­acetonato)­uranium(IV) complex of the Schiff base N,N′‐bis(3‐hydroxy­salicyl­idene)‐2‐methyl‐1,2‐propane­di­amine

The title complex, bis­(acetyl­acetonato‐κ²O,O′)[N,N′‐bis(3‐hydroxy‐2‐oxidobenzaldimino)‐2‐methyl‐1,2‐propane­di­amine‐κ⁴N,O,O′,N′]­uranium(IV) tetra­hydro­furan solvate, [U(C₁₈H₁₈N₂O₄)(C₅H₇O₂)₂]·C₄H₈O, is a rare example of a uranium(IV) complex with a compartmental Schiff base. The U atom is located in the N₂O₂ inner site of the hexadentate N,N′‐bis(3‐hydroxy‐2‐oxidobenzaldimino)‐2‐methyl‐1,2‐pro­pane­di­amine group and is bound also to the two O atoms of both acetyl­acetonate moieties, which results in a dodecahedral coordination environment. Centrosymmetric dimers are formed through intermolecular hydrogen bonds that link the terminal uncoordinated hydroxy groups to one another and to the O atoms of the acetyl­acetonate ligands.     

Diamagnetic susceptibility of spin-triplet ferromagnetic superconductors

We calculate the diamagnetic susceptibility in zero external magnetic field above the phase transition from ferromagnetic phase to phase of coexistence of ferromagnetic order and unconventional superconductivity. For this aim we use generalized Ginzburg-Landau free energy of unconventional ferromagnetic superconductor with spin-triplet electron pairing. A possible application of the result to some intermetallic compounds is briefly discussed.     

Nucleation and polymorphism explored via an easy-to-use microfluidic tool

We present an easy-to-use microfluidic set-up, easily transferable to the laboratory and determine an accurate method for metastable zone width measurement. We clearly define a zone in the phase diagram where nucleation is mononuclear. We nucleate a single crystal of metastable phase, which turns out to be stable. This approach holds promise for the control and the study of crystallization processes.