5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor.

The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J.

p-Xylene-selective metal-organic frameworks: a case of topology-directed selectivity.

Para-disubstituted alkylaromatics such as p-xylene are preferentially adsorbed from an isomer mixture on three isostructural metal-organic frameworks: MIL-125(Ti) ([Ti(8)O(8)(OH)(4)(BDC)(6)]), MIL-125(Ti)-NH(2) ([Ti(8)O(8)(OH)(4)(BDC-NH(2))(6)]), and CAU-1(Al)-NH(2) ([Al(8)(OH)(4)(OCH(3))(8)(BDC-NH(2))(6)]) (BDC = 1,4-benzenedicarboxylate). Their unique structure contains octahedral cages, which can separate molecules on the basis of differences in packing and interaction with the pore walls, as well as smaller tetrahedral cages, which are capable of separating molecules by molecular sieving. These experimental data are in line with predictions by molecular simulations.

How linker's modification controls swelling properties of highly flexible iron(III) dicarboxylates MIL-88.

A series of organically modified iron(III) terephthalate MIL-88B and iron(III) 4,4'-biphenyl dicarboxylate MIL-88D flexible solids have been synthesized and characterized through a combination of X-ray diffraction, IR spectroscopy, and thermal analysis (MIL stands for Material from Institut Lavoisier). The swelling amplitude of the highly flexible MOFs tuned by introducing functional groups onto the phenyl rings shows a clear dependence on the steric hindrance and on the number of groups per aromatic ring. For instance, while the introduction of four methyl groups per spacer in dried MIL-88B results in a large permanent porosity, introducing two or four methyl groups in MIL-88D allows an easier pore opening in the presence of liquids without drastically decreasing the swelling magnitude.

New functionalized flexible Al-MIL-53-X (X = -Cl, -Br, -CH3, -NO2, -(OH)2) solids: syntheses, characterization, sorption, and breathing behavior.

Five new flexible functionalized aluminum hydroxo terephthalates [Al(OH)(BDC-X)]·n(guests) (BDC = 1,4-benzene-dicarboxylate; X = -Cl, 1-Cl; -Br, 2-Br; -CH(3), 3-CH(3); -NO(2), 4-NO(2); -(OH)(2), 5-OH(2)) were synthesized under solvothermal conditions. The as synthesized (Al-MIL-53-X-AS) as well as the activated compounds were characterized by X-ray powder diffraction (XRPD), IR spectroscopy, thermogravimetric (TG), and elemental analysis. Activation, that is, removal of unreacted H(2)BDC-X molecules and/or occluded solvent molecules, followed by hydration in air at room temperature, led to the narrow pore (NP) form of the title compounds [Al(OH)(BDC-X)]·n(H(2)O) (Al-MIL-53-X).

Crystal-like microporous hybrid solid nanocast from Cr-MIL-101.

A crystal-like ordered microporous inorganic hybrid solid was prepared using silane functionalized Cr-MIL-101 (Si-MIL-101) as the precursor, via a surface coating reinforced framework strategy.

Poly[(μ(3)-benzene-1,3,5-tricarboxyl-ato-κO:O:O)(μ(2)-2-methyl-imidazolato-κN:N')tris-(2-methyl-imidazole-κN)dizinc(II)].

Hydro-thermal reaction involving zinc nitrate hexa-hydrate, tris-odium benzene-1,3,5-tricarboxyl-ate (Na(3)BTC) and 2-methyl-imidazole (2-MeImH) yielded the title compound, [Zn(2)(C(9)H(3)O(6))(C(4)H(5)N(2))(C(4)H(6)N(2))(3)]. In this mixed-ligand metal-organic compound, Zn(2+) ions are coordinated by N atoms from 2-MeImH mol-ecules and (2-MeIm)(-) ions, as well as by O atoms from (BTC)(3-) ions. This results in two different distorted tetra-hedra, viz.

Investigation of porous Ni-based metal-organic frameworks containing paddle-wheel type inorganic building units via high-throughput methods.

In the search of Ni based metal-organic frameworks (MOFs) containing paddle-wheel type building units, three chemical systems Ni(2+)/H(n)L/base/solvent with H(n)L = H(3)BTC (1,3,5-benzenetricarboxylic acid), H(3)BTB (4,4',4'',-benzene-1,3,5-triyl-tris(benzoic acid)), and H(2)BDC (terephthalic acid) were investigated using high-throughput (HT) methods. In addition to the conventional heating, for the first time HT microwave assisted synthesis of MOFs was carried out. Six new compounds were discovered, and their fields of formation were established.

High-throughput and time-resolved energy-dispersive X-ray diffraction (EDXRD) study of the formation of CAU-1-(OH)2: microwave and conventional heating.

Aluminium dihydroxyterephthalate [Al(8)(OH)(4)(OCH(3))(8)(BDC(OH)(2))(6)]⋅x H(2)O (denoted CAU-1-(OH)(2)) was synthesized under solvothermal conditions and characterized by X-ray powder diffraction, IR spectroscopy, sorption measurements, as well as thermogravimetric and elemental analysis. CAU-1-(OH)(2) is isoreticular to CAU-1 and its pores are lined with OH groups. It is stable under ambient conditions and in water, and it exhibits permanent porosity and two types of cavities with effective diameters of approximately 1 and 0.

The first porous MOF with photoswitchable linker molecules.

We synthesized a porous twofold interpenetrated MOF [Zn(2)(NDC)(2)(1)] (coined CAU-5) using 3-azo-phenyl-4,4'-bipyridine (1), 2,6-naphthalenedicarboxylic acid, and Zn(NO(3))(2)·6H(2)O. The azo-functionality protrudes into the pores, and can be switched, by irradiation with UV light (365 nm), from the thermodynamically stable trans-isomer to the cis-isomer. Back-switching was achieved thermally and with an irradiation wavelength of λ(max) = 440 nm.

A three-dimensional tin(II) phosphonatobenzenesulfonate with Sn4O12 clusters.

The hydrothermal reaction of SnCl(2)·2H(2)O with 4-phosphonobenzenesulfonic acid (H(3)L) and sodium hydroxide has yielded the title compound, poly[μ-hydroxido-μ(7)-(4-phosphonatobenzenesulfonato)-ditin(II)], [Sn(2)(C(6)H(4)O(6)PS)(OH)](n). The inorganic building unit is an Sn(4)O(12) cluster which is composed of edge-sharing SnO(4) and SnO(5) polyhedra. The clusters are interconnected via P and S atoms from the organic acid to form layers in the ab plane.

Nucleic acid quality preservation by an alcohol-based fixative: comparison with frozen tumors in a routine pathology setting.

Pathologic diagnosis requires tissue fixation for histologic and immunohistologic analysis, and formalin is routinely used for this. The disadvantage of this fixative is its inability to preserve nucleic acids. Pathologic tumor diagnosis requires extensive molecular analyses, for which formalin fixation may be not adequate.

Direct covalent post-synthetic chemical modification of Cr-MIL-101 using nitrating acid.

For the first time, functionality has been covalently introduced into the Cr-MIL-101 network by post-synthetic modification of the terephthalate linker molecule through nitration. The nitro group was reduced and the amino group was reacted with ethyl isocyanate to yield the corresponding urea derivative.

Sodium [2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4'-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetate (AM432): a potent, selective prostaglandin D2 receptor antagonist.

Compound 21 (AM432) was identified as a potent and selective antagonist of the DP(2) receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP(2) receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing.

[Study of the expression of Aurora kinases in renal cell carcinoma].

Objectives: The Aurora kinase family plays a crucial role in the regulation of mitosis. Over-expression of Aurora A and B has been reported in many malignant tumors. The objective of this study was to analyze the expression of Aurora A and B in renal cell carcinoma (RCC) and its correlation with usual clinical and pathological parameters.

Systematic and in situ energy dispersive X-ray diffraction investigations on the formation of lanthanide phosphonatobutanesulfonates: Ln(O(3)P-C(4)H(8)-SO(3))(H(2)O) (Ln = La-Gd).

Using the flexible linker H(2)O(3)P-C(4)H(8)-SO(3)H (H(3)L) and rare earth ions Ln(3+) (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd) we were able to synthesize the new isostructural inorganic organic hybrid compounds Ln(O(3)P-C(4)H(8)-SO(3))(H(2)O). High-throughput experiments were employed to study the influence of the molar ratios Ln:H(3)L and pH on the product formation. The crystal structure of the compounds Sm(O(3)P-C(4)H(8)-SO(3))(H(2)O) (1) and Pr(O(3)P-C(4)H(8)-SO(3))(H(2)O) (2) were determined by single crystal diffraction.

Reinvestigation of the M(II) (M = Ni, Co)/tetrathiafulvalenetetracarboxylate system using high-throughput methods: isolation of a molecular complex and its single-crystal-to-single-crystal transformation to a two-dimensional coordination polymer.

A high-throughput methodology combined with X-ray powder diffraction measurements was used to investigate the reactivity of the TetraThiaFulvalene TetraCarboxylic acid ((TTF-TC)H(4)) with divalent metals (M = Ni, Co) under various reaction conditions (stoichiometry, pH, temperature). Two new crystalline phases were identified and then studied by single crystal X-ray diffraction. Whereas the first one appears to be a simple salt, the second one, formulated {[M(H(2)O)(4)](2)(TTF-TC)}·4H(2)O, is built of 2:1 M:TTF-TC molecular complexes and labeled MIL-136(Ni, Co) (MIL stands for Materials Institute Lavoisier).

High-throughput aided synthesis of the porous metal-organic framework-type aluminum pyromellitate, MIL-121, with extra carboxylic acid functionalization.

A new porous metal-organic framework (MOF)-type aluminum pyromellitate (MIL-121 or Al(OH)[H(2)btec]·(guest), (guest = H(2)O, H(4)btec = pyromellitic acid) has been isolated by using a high-throughput synthesis method under hydrothermal conditions. Its structure was determined from powder X-ray diffraction analysis using synchrotron radiation (Soleil, France) and exhibits a network closely related to that of the MIL-53 series. It is a three-dimensional (3D) framework containing one-dimensional (1D) channels delimited by infinite trans-connected aluminum-centered octahedra AlO(4)(OH)(2) linked through the pyromellitate ligand.

The biology of melanoma prognostic factors.

Cutaneous melanoma still represents a paradox among all solid tumors. It is the cancer for which the best prognostic markers ever identified in solid tumors are available, yet there is very little understanding of their biological significance. This review focuses on recent biological data that shed light on the clinical-biological correlations underlining the 2010 American Joint Committee on Cancer (AJCC) melanoma staging system.

3-D coordination polymers based on the tetrathiafulvalenetetracarboxylate (TTF-TC) derivative: synthesis, characterization, and oxidation issues.

The reactivity of the redox-active tetracarboxylic acid derived from the tetrathiafulvalene (TTF-TC)H(4) with alkaline cations (K, Rb, Cs) is reported. The exploration of various experimental parameters (temperature, pH) led to the formation of four crystalline three-dimensional coordination polymers formulated M(2)(TTF-TC)H(2) (M = K, Rb, Cs), denoted MIL-132(K), MIL-133(isostructural K, Rb), and MIL-134(Cs). Thermogravimetric analysis and thermodiffraction show that all of the solids are thermally stable up to 150-200 degrees C in the air.

5-Lipoxygenase-activating protein inhibitors. Part 3: 3-{3-tert-Butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM643)-A potent FLAP inhibitor suitable for topical administration.

AM643 (compound 6, 3-{3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid) was identified as a potential candidate for formulation as a topical agent for the treatment of skin disorders involving leukotriene production. Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling.

Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation.

We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.

Oriented growth of the functionalized metal-organic framework CAU-1 on -OH- and -COOH-terminated self-assembled monolayers.

The oriented growth of the amino-functionalized metal-organic framework [Al4(OH)2(OCH3)4(H2N-bdc)3].xH2O (named CAU-1; CAU = Christian-Albrechts-University) on different self-assembled monolayers (SAMs) is reported. Gold substrates were modified with both 16-mercaptohexadecanol and 16-mercaptohexadecanoic acid SAMs and immersed in a pre-treated crystallization solution.

Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists.

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.