Stepwise and dramatic enhancement of anion recognition with a triple-site receptor based on the calix[4]arene framework using two different cationic effectors

Synthesis and binding behavior of a novel multi-responsive host 1, in which two esters, two polyether moieties, two urea sites, and two bipyridine units as ion binding sites are arranged on the calix[4]arene skeleton, is reported. 1 recognizes Na(+) and Ag(+) simultaneously and quantitatively and captures an anionic guest. The ability of 1 to recognize anions, including CF(3)SO(3)(-) and BF(4)(-), remarkably increases in a stepwise manner using Na(+) and Ag(+) as effectors. The enhancement of the K(a) eventually reaches factors of 1500 and 2000 for NO(3)(-) and CF(3)SO(3)(-), respectively, in the presence of both Na(+) and Ag(+), compared to the free 1. The regulation of binding of multiple ligands may be applicable to multistep cascade systems for the amplification of molecular events, and further studies in this field could provide insight applicable to more advanced molecular devices.     

Cationic ring-opening polymerization of 1,4-anhydro-2,3-di-O-benzyl-α-L-arabinopyranose and synthesis of L-arabinofuranan

1,4-Anhydro-2,3-di-O-benzyl-α-L -arabinopyranose (=1,5-anhydro-2,3-di-O-benzyl-β-L -arabinofuranose) (ABAP) was synthesized and underwent cationic ring-opening polymerization with several kinds of Lewis acids. All the polylmers prepared by Lewis acids as catalyst were found to consist of two different structural units, α-furanosidic and β-furanosidic units, and the structure of the polymers greatly depended on the polymerization conditions. Polymerization of ABAP with antimony pentachloride catalyst at 0°C for 42 h gave a polymer with the highest α content of 93%, and that at ?20°C for 3 h gave a polymer with the lowest (25%) α content. The other catalysts such as phosphorus pentafluoride, boron trifluoride etherate, niobium pentafluoride, and tantalum pentafluoride also afforded polymers with mixed structure of α-and β-furanosides. After debenzylation of poly(ABAP), a new polysaccharide, L -arabinofuranan was obtained.     

Reaction of poly(vinyl chloride) with magnesium and grignard reagents

Reaction of poly(vinyl chloride) with magnesium under various conditions was attempted, but poly(vinyl chloride) did not react with magnesium. The reactions of poly(vinyl chloride) with benzylmagnesium chloride and allylmagnesium chloride as Grignard reagents were carried out in tetrahydrofuran at reflux temperature. It was found that the chlorine atoms in the poly(vinyl chloride) were replaced by benzyl and allyl groups by the coupling reaction, and a small amount of Grignard reagent of poly(vinyl chloride) was formed by the magnesium–halogen exchange reaction. The extent of the substitution increased with increasing reaction time and concentration of the Grignard reagent.     

One-step analysis of testis steroidogenesis from neonatal exposure to synthetic estrogen by normal-phase HPLC

Neonatal exposure to synthetic estrogen endocrine disruptors or estrogen-receptor inhibitors induces developmental abnormalities in the male reproductive system. To investigate whether neonatal exposure affects spermatogenesis in juvenile and pubertal testis, Sprague-Dawley rat pups were given synthetic estrogen endocrine disruptors or estrogen-receptor inhibitors by a single injection on the day of birth at concentrations ranging between 2 to 40 mm, and sacrificed on day 21 (juvenile), 35 (prepuberty) or 50 (puberty). The testes were weighed and examined histologically at each stage. Further, the metabolites of steroidogenesis were analyzed using normal-phase high performance liquid chromatography. Neonatal exposure significantly reduced testis weights and steroidogenesis to one- fifth to one-half of that of the juvenile control, and further suppressed irreversible steroidogenesis and spermatogenesis during puberty.     

Preparation of prolonged-release spherical micro-matrix of ibuprofen with acrylic polymer by the emulsion-solvent diffusion method for improving bioavailability

Prolonged-release spherical micro-matrices of ibuprofen with acrylic polymer (Eudragit RS) were prepared using a novel emulsion-solvent diffusion method. It was found by examining cross sections of the spherical matrix before and after dissolution tests with a scanning electron microscope and a porosimeter that the resultant micro-matrix had a sponge-like internal structure. The spherical matrices were successfully recovered with a relatively high concentration of the drug in ethanol (0.4-0.6 g/ml) and over a wide range of temperatures (5-35 degrees C). The size of the spherical matrix could be easily controlled by varying the agitation speed of the system and the concentration of emulsifier added to the aqueous medium. The drug release rate from the spherical matrix decreased with increasing concentration of polymer formulated due to the reduced diffusion path and increased tortuosity in the matrix. Spherical matrices with ibuprofen:Eudragit RS = 3:1 improved the bioavailability of the drug and prolonged the drug action in beagle dogs.     

Regulation of geometry around the ruthenium center of bis(2-pyridinecarboxylato) complexes by the nitrosyl moiety: syntheses, structures, and theoretical studies

cis-[Ru(NO)Cl(pyca)(2)] (pyca = 2-pyridinecarboxylato), in which the two pyridyl nitrogen atoms of the two pyca ligands coordinate at the trans position to each other and the two carboxylic oxygen atoms at the trans position to the nitrosyl ligand and the chloro ligand, respectively (type I shown as in Chart 1), reacted with NaOCH(3) to generate cis-[Ru(NO)(OCH(3))(pyca)(2)] (type I). The geometry of this complex was confirmed to be the same as the starting complex by X-ray crystallography: C(13.5)H(13)N(3)O(6.5)Ru; monoclinic, P2(1)/n; a = 8.120(1), b = 16.650(1), c = 11.510(1) A; beta = 99.07(1) degrees; V = 1536.7(2) A(3); Z = 4. The cis-trans geometrical change reaction occurred in the reactions of cis-[Ru(NO)(OCH(3))(pyca)(2)] (type I) in water and alcohol (ROH, R = CH(3), C(2)H(5)) to form [[trans-Ru(NO)(pyca)(2)](2)(H(3)O(2))](+) (type V) and trans-[Ru(NO)(OR)(pyca)(2)] (type V). The reactions of the trans-form complexes, trans-[Ru(NO)(H(2)O)(pyca)(2)](+) (type V) and trans-[Ru(NO)(OCH(3))(pyca)(2)] (type V), with Cl(-) in hydrochloric acid solution afforded the cis-form complex, cis-[Ru(NO)Cl(pyca)(2)] (type I). The favorable geometry of [Ru(NO)X(pyca)(2)](n)(+) depended on the nature of the coexisting ligand X. This conclusion was confirmed by theoretical, synthetic, and structural studies. The mono-pyca-containing nitrosylruthenium complex (C(2)H(5))(4)N[Ru(NO)Cl(3)(pyca)] was synthesized by the reaction of [Ru(NO)Cl(5)](2)(-) with Hpyca and characterized by X-ray structural analysis: C(14)H(24)N(3)O(3)Cl(3)Ru; triclinic, Ponemacr;, a = 7.631(1), b = 9.669(1), c = 13.627(1) A; alpha = 83.05(2), beta = 82.23(1), gamma = 81.94(1) degrees; V = 981.1(1) A(3); Z = 2. The type II complex of cis-[Ru(NO)Cl(pyca)(2)] was synthesized by the reaction of [Ru(NO)Cl(3)(pyca)](-) or [Ru(NO)Cl(5)](2)(-) with Hpyca and isolated by column chromatography. The structure was determined by X-ray structural analysis: C(12)H(8)N(3)O(5)ClRu; monoclinic, P2(1)/n; a = 10.010(1), b = 13.280(1), c = 11.335(1) A; beta = 113.45(1) degrees; V = 1382.4(2) A(3); Z = 4.     

Synthesis and calcium antagonistic activity of (+)-(R)- and (-)-(S)-3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5- trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline hydrochloride

SA2572 ((+)-1), 3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl) amino] butoxy]phenyl]-benzothiazoline hydrochloride is a newly synthesized Ca2+ antagonist having a inhibitory effect on the fast Na+ inward channel. In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca2+ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca2+ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na+ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca2+ inward channel as compared with compound (-)-1. Stereoselectivity of the pharmacological activity was found.     

Molecular interactions between lipid bilayers and a water-soluble polymer

Molecular interactions between lipid bilayers (liposomes) and chondroitin sulfate C (CS), a water soluble polymer, have been investigated in terms of zeta-potential, particle size, microscopic-viscosity, microscopic-polarity of liposomes and permeability of calcein. Microscopic morphology is dramatically changed by the addition of CS to the positively charged liposomes (Pos.L), while it is not changed by the addition to uncharged liposomes (Unc.L) or negatively charged liposomes (Neg.L). The absolute value of the particle size of Pos.L increases with the addition of CS, while the zeta- potential of Pos.L decreases. Permeability of Pos.L decreases with an increase in the concentration of CS. Phase transition temperature of Pos.L is changed after the addition of CS. These values, however, are not changed for the other liposomes by the addition of CS. The results of gel filtration chromatography show that CS is absorbed on the Pos.L surface. Microscopic viscosity is also increased by the addition of CS to Pos.L due to the adsorption of CS.     

Y-931, a novel atypical antipsychotic drug,is less sensitive to oxidative phenomena

The oxidation behavior of Y-931, a potent atypical antipsychotic drug, was compared with that of clozapine and olanzapine. In two enzymatic systems (horseradish peroxidase (HRP)/glutathione (GSH) and HRP/H(2)O(2)/GSH) which generate thiyl radicals, clozapine markedly strengthened the electron paramagnetic resonance (EPR) signal for the radical. Olanzapine, Y-931 and the major metabolites (compounds 1-3) had no or minimal effect on the intensity of this signal. In addition, the redox potential values for the three derivatives were in accord with the EPR spin trapping results. In toxicological experiments in human leukocytes, a concentration-dependent toxicity was observed when neutrophils were incubated with clozapine (1-10 micromol/l) and H(2)O(2) (1 mmol/l). However, Y-931 and olanzapine did not show remarkable toxicity under the conditions.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H[1]benzothiopyrano[3,2-B]pyridine and 7-oxo-7,13-dihydro[1]benzothiopyrano[2,3-b]-1,5-benzodiazepine

3-Amino-4H-1-benzothiopyran-4-one (3-aminothiochromone) was easily prepared by reaction of 3-bromo-thiochromen-4-one with sodium azide in methanol-water. Condensation of 3-aminothiochromone with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate gave intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-1H[1]benzothiopyrano[3,2-b]pyridinecarboxylates. 3-Formyl-thiochromone was condensed with o-phenylenediamine to give 7-oxo-7,13-dihydro[1]benzothiopyrano[2,3-b]-1,5-benzodiazepine.