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First Compound (first + compound)
Selected AbstractsA Vacuolar ATPase Inhibitor, FR167356, Prevents Bone Resorption in Ovariectomized Rats With High Potency and Specificity: Potential for Clinical Application,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2005Kazuaki Niikura MS Abstract FR167356, a novel inhibitor of vacuolar ATPase, has high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. FR167356 is the first compound of this nature to be tested. It has the potential to be useful for clinical application. Introduction: It has been suggested that the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity. Materials and Methods: In in vitro and in vivo studies, we compared FR167356 with other vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 and SB242784. H+ transport by various membrane vesicles was assayed by measuring uptake of acridine orange. Inhibitory activity against in vitro bone resorption was examined by measuring the Ca2+ release from cultured calvariae. In vivo, hypercalcemia was induced by retinoic acid in thyroparathyroidectomized-ovariectomized rats, and the effect on serum Ca2+ level was assessed. Ovariectomized rats were treated with FR167356 or SB242784. One week after surgery, free deoxypyridinoline levels in 24-h urine samples, which were collected from 6 h after administration of FR167356, were measured by ELISA. After 4 weeks of treatment, plasma biochemical parameters were analyzed. BMD of the distal femur metaphysis was measured with pQCT. Histomorphometric analysis of the proximal tibias was performed. Blood gases of rats treated with FR167356 were measured with a blood gas analyzer for estimating the effect of FR167356 on in vivo function of renal V-ATPase. Results: FR167356, which is distinctly different from other V-ATPase inhibitors, has a high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. Similarly, FR167356 inhibited bone resorption in vitro when stimulated by PTH, IL-1, and IL-6. FR167356 reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats in a dose-dependent manner. Moreover, FR167356 was shown to restore BMD of ovariectomized rats caused by the inhibition of bone resorption. Ovariectomized rats treated with FR167356 did not show adverse symptoms, whereas SB242784 caused a decrease in body weight gain and significant changes in two plasma biochemical parameters. Interestingly, FR167356 treatment did not affect blood acid-base balance; however, FR167356 inhibited renal V-ATPase with a similar potency as for osteoclast V-ATPase inhibition. Conclusion: Comparison of FR167356 with SB242784 implies that the characteristics of FR167356 may be more appropriate for clinical application as a V-ATPase inhibitor. [source] Simultaneous inhibition of anti-coagulation and inflammation: crystal structure of phospholipase A2 complexed with indomethacin at 1.4,Å resolution reveals the presence of the new common ligand-binding siteJOURNAL OF MOLECULAR RECOGNITION, Issue 6 2009Nagendra Singh Abstract A novel ligand-binding site with functional implications has been identified in phospholipase A2 (PLA2). The binding of non-steroidal anti-inflammatory agent indomethacin at this site blocks both catalytic and anti-coagulant actions of PLA2. A group IIA PLA2 has been isolated from Daboia russelli pulchella (Russell's viper) which is enzymatically active as well as induces a strong anti-coagulant action. The binding studies have shown that indomethacin reduces the effects of both anti-coagulant and pro-inflammatory actions of PLA2. A group IIA PLA2 was co-crystallized with indomethacin and the structure of the complex has been determined at 1.4,Å resolution. The structure determination has revealed the presence of an indomethacin molecule in the structure of PLA2 at a site which is distinct from the conventional substrate-binding site. One of the carboxylic group oxygen atoms of indomethacin interacts with Asp 49 and His 48 through the catalytically important water molecule OW 18 while the second carboxylic oxygen atom forms an ionic interaction with the side chain of Lys 69. It is well known that the residues, His 48 and Asp 49 are essential for catalysis while Lys 69 is a part of the anti-coagulant loop (residues, 54,77). Indomethacin binds in such a manner that it blocks the access to both, it works as a dual inhibitor for catalytic and anti-coagulant actions of PLA2. This new binding site in PLA2 has been observed for the first time and indomethacin is the first compound that has been shown to bind at this novel site resulting in the prevention of anti-coagulation and inflammation. Copyright © 2009 John Wiley & Sons, Ltd. [source] Dipole moments of polyenic oligomeric systems.JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 9 2005Part II, allenes, molecular organic wire resistivities: polyacetylenes, polyynes Abstract Polyacetylenic, allenic and polyynic molecular wire series, containing electron-donor (D) and electron-acceptor (A) groups as two terminal units of the oligomeric bridge (D,wire,A), can be well described by means of a one-dimensional conduction model, which considers a scattering process of electrons through the charge-transfer conduction bridge. The conduction constants (,i) of the oligomeric structures of the three molecular series under study were determined from the functional dependence between the dipole moment of the oligomers (,n) and the ,-molecular orbital bridge length (L). According to our one-dimensional molecular organic wire model: where ,o is the dipolar moment of the first compound of the oligomeric series without a bridge unit (n,=,0) and ,, is a limit value for L,,,,. By means of the Landauer theoretical expression for the conductance of a metallic one-dimensional conductor and our molecular wire conduction constants (,i), we determined the intrinsic resistivities associated with the molecular resistances of these oligomeric wires. Using this approach we determined, for the first time, the linear and non-linear contributions to the net molecular resistivity. The order of magnitudes of the linear resistivities determined in these oligomeric systems agrees very well with the expected results of experimental measurements for macroscopic wires. Copyright © 2005 John Wiley & Sons, Ltd. [source] Structural analysis of 3-,-acetyl-20(29)-lupene-24-oic acid, a novel pentacyclic triterpene isolated from the gum resin of Boswellia serrata, by NMR spectroscopyMAGNETIC RESONANCE IN CHEMISTRY, Issue 8 2003Klaus Belsner Abstract 3,-Acetyl-20(29)-lupene-24-oic acid (1) was isolated from the gum resin of Boswellia serrata. Its presence evidently suggests, that the oxidosqualene triterpene pathway of Boswellia serrata closely resembles the biosynthetic route already found in other plants. Complete 1H and 13C spectral assignments were derived from 1D and 2D NMR spectra. This is the first compound with the lupene backbone combining a 3,-hydroxy or 3,-acetyl group with the 24-carboxyl group, a configuration which is typical of the classical boswellic acids. Copyright © 2003 John Wiley & Sons, Ltd. [source] Halogen, hydrogen and electrostatic interactions in 2-amino-5-chloro-1,3-benzoxazol-3-ium nitrate and 2-amino-5-chloro-1,3-benzoxazol-3-ium perchlorateACTA CRYSTALLOGRAPHICA SECTION C, Issue 9 2010Rafal Kruszynski In the title compounds, C7H6ClN2O+·NO3, and C7H6ClN2O+·ClO4,, the ions are connected by N,H...O hydrogen bonds and halogen interactions. Additionally, in the first compound, co-operative ,,, stacking and halogen..., interactions are observed. The energies of the observed interactions range from a value typical for very weak interactions (1.80,kJ,mol,1) to one typical for mildly strong interactions (53.01,kJ,mol,1). The iminium cations exist in an equilibrium form intermediate between exo- and endocyclic. This study provides structural insights relevant to the biochemical activity of 2-amino-5-chloro-1,3-benzoxazole compounds. [source] Bifunctional Catalysis by Natural Cinchona Alkaloids: A Mechanism ExplainedCHEMISTRY - A EUROPEAN JOURNAL, Issue 32 2009Clotilde Abstract The use of bifunctional chiral catalysts, which are able to simultaneously bind and activate two reacting partners, currently represents an efficient and reliable strategy for the stereoselective preparation of valuable chiral compounds. Cinchona alkaloids such as quinine and quinidine, simple organic molecules generously provided by Nature, were the first compounds to be proposed to operate through a cooperative catalysis. To date, a full mechanistic characterization of the dual catalysis mode of cinchona alkaloids has proven a challenging objective, due to the transient, non-covalent nature of the involved catalyst,substrate interactions. Here, we propose a mechanistic rationale on how natural cinchona alkaloids act as efficient bifunctional catalysts by using a broad range of computational methods, including classical molecular dynamics, a mixed quantum mechanical/molecular mechanics (QM/MM) approach, and correlated ab-initio calculations. We also unravel the origin of enantio- and diastereoselectivity, which is due to a specific network of hydrogen bonds that stabilize the transition state of the rate-determining step. The results are validated by experimental evidence. [source] | ||||||||||