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New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim-3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The synthesis and Pim kinase inhibition potency of a new series of pyrrolo[2,3-g]indazole derivatives is described. The results obtained in this preliminary structure-activity relationship study pointed out that sub-micromolar Pim-1 and Pim-3 inhibitory potencies could be obtained in this series, more particularly for compounds 10 and 20, showing that pyrrolo[2,3-g]indazole scaffold could be used for the development of new potent Pim kinase inhibitors. Molecular modeling experiments were also performed to study the binding mode of these compounds in Pim-3 ATP-binding pocket., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

New trisdipicolinic acid-lanthanide complexes are reported as phasing agents for X-ray crystallography of proteins. It is demonstrated that CuAAC modifications allow protein co-crystallization with low concentration of lanthanide complexes leading to an accurate structure determination.

Pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis and biological activities (Pim kinase inhibition and in vitro antiproliferative potency) of new 4-substituted pyrrolo[2,3-a]carbazoles. The results demonstrated that the Pim kinase inhibitory potency (especially Pim-3) can be conserved for pyrrolo[2,3-a]carbazoles bearing a methoxycarbonyl group at the 4-position without a formyl at the 3-position. Moreover, compound 27 that was found to be active against Pim-1 and Pim-3 kinases showed antiproliferative activities in the micromolar range., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A new strategy was developed for the modification of silver(I) and gold(I) N-heterocyclic carbenes. Azido groups were grafted and used either by copper-catalysed azide-alkyne cycloaddition before metallation or by thermal and "strain-promoted" 1,3-dipolar cycloaddition after metallation to functionalise the metal-NHCs.

Di- and trimeric quinoline derivatives have been recently described as potential modulators of Bcl-2 family protein interactions. However, only a few trimeric compounds have been described so far and an enlargement of the number of analogs of this class is needed to expand the structure-activity relationship study. Therefore, the synthesis of six new trimeric quinoline derivatives is reported. Moreover molecular modeling experiments were performed to study the conformational arrangement of compound 36 in Bak binding site of Bcl-x(L), showing that these compounds could be potential ligands for Bcl-x(L)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A platinum Chugaev complex was synthesised and fully characterized by multinuclear NMR spectroscopy and X-ray crystallography. This cis bis acyclic diamino carbene complex acts as a cytotoxic compound and behaves as a cisplatin equivalent by interacting with supercoiled DNA and thiols. Stability of the ligand is also discussed.

The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as well as some of their synthetic intermediates were tested for their kinase inhibitory potencies and for their in vitro antiproliferative activities. We found that this series of compounds is particularly interesting in the development of new inhibitors of DYRK1A and CLK1 kinases. The most effective compounds toward these two kinase families are the 6- and 7-bromo derivatives 30, 33, and 34 that showed more than 45-fold selectivity toward DYRK1A/CLK1 kinases over the other kinases tested. Meridianin derivatives could thus be developed toward potent and selective inhibitors of key RNA splicing regulators and potential therapeutic agents.

The synthesis of new pyrrolo[2,3-a]carbazole derivatives diversely substituted at the C-6 to C-9 positions is described. These compounds were tested for their kinase inhibitory potencies toward three kinases (Pim-1, Pim-2, Pim-3) as well as for their in vitro antiproliferative activities toward a human fibroblast primary culture and three human solid cancer cell lines (PC3, DU145, and PA 1). Moreover, molecular docking studies were performed to explain the enhanced inhibitory activity of the most active compound 3d., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Crystal diffraction of three membrane proteins (cytochrome bc(1) complex, sarcoplasmic reticulum Ca(2+) ATPase, ADP-ATP carrier) and of one nucleoprotein complex (leucyl tRNA synthetase bound to tRNAleu, leuRS:tRNAleu) was tested at wavelengths near the X-ray K-absorption edge of phosphorus using a new set-up for soft X-ray diffraction at the beamline ID01 of the ESRF. The best result was obtained from crystals of Ca(2+) ATPase [adenosin-5'-(beta,gamma-methylene) triphosphate complex] which diffracted out to 7 A resolution. Data were recorded at a wavelength at which the real resonant scattering factor of phosphorus reaches the extreme value of -20 electron units. The positions of the four triphosphates of the monoclinic unit cell of the ATPase have been obtained from a difference Fourier synthesis based on a limited set of anomalous diffraction data.

One mechanism by which bacteria can escape the action of beta-lactam antibiotics is the production of metallo-beta-lactamases. Inhibition of these enzymes should restore the action of these widely used antibiotics. The tetrameric enzyme L1 from Stenotrophomonas maltophilia was used as a model system to determine a series of high-resolution crystal structures of apo, mono and bi-metal substituted proteins as well as protein-inhibitor complexes. Unexpectedly, although the apo structure revealed only few significant structural differences from the holo structure, some inhibitors were shown to induce amino acid side-chain rotations in the tightly packed active site. Moreover, one inhibitor employs a new binding mode in order to interact with the di-zinc center. This structural information could prove essential in the process of elucidation of the mode of interaction between a putative lead compound and metallo-beta-lactamases, one of the main steps in structure-based drug design.

Phosphorus is an abundant element in living organisms. It is traceable by its X-ray absorption spectrum which shows a strong white line at its K-edge, comparable with that observed for the L(III) edges of rare earth ions. With purple membrane, the variation of the imaginary part of the anomalous dispersion of phosphorus is found to be close to 20 anomalous electron units. Anomalous diffraction experiments at wavelengths near the K-absorption edge of phosphorus confirm this result. The spatial distribution of lipids derived from anomalous diffraction agrees with earlier results from neutron diffraction. Test experiments on single crystals of the carrier protein using 5.76 A photons gave a first low-resolution diffraction pattern. Various techniques of crystal mounting were attempted. In addition, fluorescence measurements on a solution of threonine synthase appear to hint at a change of the phosphate environment of the cofactor upon activator binding.