Structures of ethylenediaminetetraacetato (3-) metal complexes. I complexes with Co, Mg and Cd metals

(I): Hexaaquacobalt(II) aqua[ethylenediaminetetraacetato(3-)]cobaltate(II) dihydrate, [Co(H2O)6][Co(C10H13N2O8)(H2O)]2.2H2O (Ibis): Hexaaquamagnesium(II) aqua[ethylenediaminetetraacetato(3-)]magnesiate(II) dihydrate, [Mg(H2O)6][Mg(C10H13N2O8)(H2O)]2.2H2O (II):Tetraaquabis{aqua[ethylenediaminetetraacetato(3-)]cadmium(II)-O-O'}Cadmium(II) tetrahydrate

Structures of ethylenediaminetetraacetato (3-) metal complexes. I complexes with Co, Mg and Cd metals

(I): Hexaaquacobalt(II) aqua[ethylenediaminetetraacetato(3-)]cobaltate(II) dihydrate, [Co(H2O)6][Co(C10H13N2O8)(H2O)]2.2H2O (Ibis): Hexaaquamagnesium(II) aqua[ethylenediaminetetraacetato(3-)]magnesiate(II) dihydrate, [Mg(H2O)6][Mg(C10H13N2O8)(H2O)]2.2H2O (II):Tetraaquabis{aqua[ethylenediaminetetraacetato(3-)]cadmium(II)-O-O'}Cadmium(II) tetrahydrate

Structures of ethylenediaminetetraacetato (3-) metal complexes. I complexes with Co, Mg and Cd metals

(I): Hexaaquacobalt(II) aqua[ethylenediaminetetraacetato(3-)]cobaltate(II) dihydrate, [Co(H2O)6][Co(C10H13N2O8)(H2O)]2.2H2O (Ibis): Hexaaquamagnesium(II) aqua[ethylenediaminetetraacetato(3-)]magnesiate(II) dihydrate, [Mg(H2O)6][Mg(C10H13N2O8)(H2O)]2.2H2O (II):Tetraaquabis{aqua[ethylenediaminetetraacetato(3-)]cadmium(II)-O-O'}Cadmium(II) tetrahydrate

Structure and function of RecA-DNA complexes.

While the E. coli RecA protein has been the most intensively studied enzyme of homologous recombination, the unusual RecA-DNA filament has stood alone until very recently. It now appears that this protein is part of a universal family that spans all of biology, and the filament that is formed by the protein on DNA is a universal structure. With RecA's role in recombination given new and greatly increased significance, we focus in this review on the energetics of the RecA-mediated strand exchange and the relation between the energetics and recombination spanning heterologous inserts.

Les antagonistes des r��cep- teurs de l'endoth��line ont-ils une place dans le traitement de l'hyper- tension art��rielle [Do endothelin receptors antagonists have a place in the treatment of arterial hypertension?].

The discovery in 1988 of endothelin, the most potent human endogenous vasoconstrictor, has opened the race to the discovery of a new weapon against arterial hypertension. The development of the endothelin receptors antagonists (ERAs) and the demonstration of their efficacy in preclinical models initially raised a wave of enthusiasm, which was however tempered due to their unfavorable side effect profile. In this article we will review the phases of the development ERAs, and their current and future place as therapeutic tool against arterial hypertension.

Migration of dissolved organic carbon in biochars and biochar-mineral complexes

The objective of this work was to determine the contribution of dissolved organic carbon (DOC) from a biochar mineral complex (BMC), so as to better understand the interactions between DOC, biochar, clay, and minerals during thermal treatment, and the effects of BMC on amended soils. The BMC was prepared by heating a mixture of a H3PO4-treated saligna biochar from Acacia saligna, clays, other minerals, and chicken manure. The BMC was applied to a sandy loam soil in Western Australia, where wheat was grown. Liquid chromatography-organic carbon detection (LC-OCD) tests were carried out on water extracts from the untreated biochar, the BMC, the BMC-amended soil, and on a control soil to measure the DOC concentration. LC-OCD tests provide a fingerprint of the DOC, which allows the fractions of DOC to be determined. Thermal processing enhanced the reaction of the A. saligna biochar with manure, clays and minerals, and affected the distribution of the DOC fractions. Notably, the process leads to immobilization of hydrophobic DOC and to an increase in the concentration of low-molecular-weight neutrals in the BMC. The application of the BMC to soil increases the DOC in the amended soil, especially the biopolymer fraction.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic ��-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor �� (TR��), in a high-throughput screen. Initial evidence suggested that the aromatic ��-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TR�� surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TR�� with the inhibitor HPPE at 2.3-�� resolution. Unreacted HPPE is located at the interface that normally mediates binding between TR�� and its coactivator. Several lines of evidence, including experiments with TR�� mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TR��, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) ��-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TR��. DHPPA represents a novel class of potent TR�� antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Anthracene-tethered ruthenium(II) arene complexes as tools to visualize the cellular localization of putative organometallic anticancer compounds.

Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported.

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10��μM) and the more potent and specific P-gp inhibitor valspodar (5��μM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50��μM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Le renouveau des antagonistes de l'atdost��rone [The revived interest in aldosterone antagonists]

Aldosterone plays a pivotal role in sodium and water homeostasis, in particular in patients with heart failure or high blood pressure. These medications, when used on top of a standard therapy, improve the outcome of patients with heart failure and are also effective in lowering blood pressure of hypertensive patients. The major risk associated with the use of these antagonists is hyperkalemia, which can be prevented in avoiding their prescription in patients with impaired renal function. Eplerenone has the advantage, compared with spironolactone, to be better tolerated in terms of "hormonal" adverse effects.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.

Blind docking of 260 protein-ligand complexes with EADock 2.0.

Molecular docking softwares are one of the important tools of modern drug development pipelines. The promising achievements of the last 10 years emphasize the need for further improvement, as reflected by several recent publications (Leach et al., J Med Chem 2006, 49, 5851; Warren et al., J Med Chem 2006, 49, 5912). Our initial approach, EADock, showed a good performance in reproducing the experimental binding modes for a set of 37 different ligand-protein complexes (Grosdidier et al., Proteins 2007, 67, 1010). This article presents recent improvements regarding the scoring and sampling aspects over the initial implementation, as well as a new seeding procedure based on the detection of cavities, opening the door to blind docking with EADock. These enhancements were validated on 260 complexes taken from the high quality Ligand Protein Database [LPDB, (Roche et al., J Med Chem 2001, 44, 3592)]. Two issues were identified: first, the quality of the initial structures cannot be assumed and a manual inspection and/or a search in the literature are likely to be required to achieve the best performance. Second the description of interactions involving metal ions still has to be improved. Nonetheless, a remarkable success rate of 65% was achieved for a large scale blind docking assay, when considering only the top ranked binding mode and a success threshold of 2 A RMSD to the crystal structure. When looking at the five-top ranked binding modes, the success rate increases up to 76%. In a standard local docking assay, success rates of 75 and 83% were obtained, considering only the top ranked binding mode, or the five top binding modes, respectively.

Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility.

The flexibility of different regions of HIV-1 protease was examined by using a database consisting of 73 X-ray structures that differ in terms of sequence, ligands or both. The root-mean-square differences of the backbone for the set of structures were shown to have the same variation with residue number as those obtained from molecular dynamics simulations, normal mode analyses and X-ray B-factors. This supports the idea that observed structural changes provide a measure of the inherent flexibility of the protein, although specific interactions between the protease and the ligand play a secondary role. The results suggest that the potential energy surface of the HIV-1 protease is characterized by many local minima with small energetic differences, some of which are sampled by the different X-ray structures of the HIV-1 protease complexes. Interdomain correlated motions were calculated from the structural fluctuations and the results were also in agreement with molecular dynamics simulations and normal mode analyses. Implications of the results for the drug-resistance engendered by mutations are discussed briefly.

Reliability of the density functional approximation to describe the charge transfer and electrostatic complexes involved in the modeling of organic conducting polymers

Both the intermolecular interaction energies and the geometries for M �� thiophene, M �� pyrrole, M n+ �� thiophene, and M n+ �� pyrrole ��with M = Li, Na, K, Ca, and Mg; and M n+ = Li+ , Na+ , K+ , Ca2+, and Mg2+�� have been estimated using four commonly used density functional theory ��DFT�� methods: B3LYP, B3PW91, PBE, and MPW1PW91. Results have been compared to those provided by HF, MP2, and MP4 conventional ab initio methods. The PBE and MPW1PW91 are the only DFT methods able to provide a reasonable description of the M �� complexes. Regarding M n+ �� ��� complexes, the four DFT methods have been proven to be adequate in the prediction of these electrostatically stabilized systems, even though they tend to overestimate the interaction energies.