Studies on the synthesis of condensed pyridazine derivatives. IV. Synthesis and anxiolytic activity of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-ones and related compound.

A series of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)- ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo. Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39--42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5,6-dihydro- (37) and 2-(4'-chlorophenyl)-5,6-dihydro-10-fluoro-(1)benzothiepino[5,4-c]+ ++pyridazin- 3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of gamma-aminobutyric acid-induced chloride current (Icl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.     

Comparative studies on the analysis of glycosylation heterogeneity of sialic acid-containing glycoproteins using capillary electrophoresis

Frontal affinity chromatography is a method for quantitative analysis of biomolecular interactions. We reinforced it by incorporating various merits of a contemporary liquid chromatography system. As a model study, the interaction between an immobilized Caenorhabditis elegans galectin (LEC-6) and fluorescently labeled oligosaccharides (pyridylaminated sugars) was analyzed. LEC-6 was coupled to N-hydroxysuccinimide-activated Sepharose 4 Fast Flow (100 μm diameter), and packed into a miniature column (e.g., 10×4.0 mm, 0.126 ml). Twelve pyridylaminated oligosaccharides were applied to the column through a 2-ml sample loop, and their elution patterns were monitored by fluorescence. The volume of the elution front (V) determined graphically for each sample was compared with that obtained in the presence of an excess amount of hapten saccharide, lactose (V₀); and the dissociation constant, K_d, was calculated according to the literature [K. Kasai, Y. Oda, M. Nishikawa, S. Ishii, J. Chromatogr. 376 (1986) 33]. This system also proved to be useful for an inverse confirmation; that is, application of galectins to an immobilized glycan column (in the present case, asialofetuin was immobilized on Sepharose 4 Fast Flow), and the elution profiles were monitored by fluorescence based on tryptophan. The relative affinity of various galectins for asialofetuin could be easily compared in terms of the extent of retardation. The newly constructed system proved to be extremely versatile. It enabled rapid (analysis time 12 min/cycle) and sensitive (20 nM for pyridylaminated derivatives, and 1 μg/ml for protein) analyses of lectin–carbohydrate interactions. It should become a powerful tool for elucidation of biomolecular interactions, in particular for functional analysis of a large number of proteins that should be the essential issues of post-genome projects.     

Cooperative C-F...Si interaction in optically active helical polysilanes

Cooperative amplification of the C-F...Si weak interaction between side chains and the main chain was found to afford rigid rodlike helical polysilanes with a preferential screw sense.     

Palladium-catalysed dimerization of vinylarenes using indium triflate as an effective co-catalyst

A palladium-indium triflate catalyst was found to be much more active for the dimerization of vinylarenes compared with generally used cationic palladium(II) catalysts.     

Thermodynamic analysis of duplex formation of the heterochiral DNA with L-deoxyadenosine.

An L-DNA, the mirror-image isomer of natural DNA, has extraordinary nuclease resistance, and thus the molecules should be promising reagents for many applications, such as antisense technology. However, little is known about the structural and thermodynamic properties of DNAs with this modified nucleotide. In this study, we prepared the L-nucleotide (L-dA) and introduced it into oligodeoxyribonucleotides to assess the ability of the L-nucleotide as a functional molecule for many applications based on the DNA hybridization. Two decamers with an L-dA at the center were synthesized and duplexes with the complementary DNA strand were applied to structural and thermodynamic analyses. The structural study by CD spectra showed that the structures of both modified "L/D-D" duplexes were the typical B-form. This result suggests that the global structure of DNA was not collapsed by the introduction of an L-DNA. Thermodynamic parameters (deltaH degrees, deltaS degrees, and deltaG degrees 37) of the duplex formation, determined by UV melting experiments, indicated that the both duplexes were destabilized at about 2.5 to 3.0 kcal mol(-1) by the introduced L-dA, mainly due to an unfavorable enthalpic effect. In conjunction with information by other researchers, these results suggest that the L-DNA affect on the duplex structure and the stability vary locally; thus, the thermodynamic stability of modified L/D-D duplexes should be predictable by the nearest-neighbor thermodynamic parameters.