1) A series of synthetic works on nucleosides appropriately labeled with stable isotopes of deuterium, carbon-13, and nitrogen-15 has been undertaken, confronting the strong demands for the nucleosides in the NMR spectroscopic study deeply related to structural biology, and the synthetic methods of (2'R)-and (2'S)-2'-deoxy[2'-2H]ribonucleosides, 2'-deoxy[5'-2H]ribonucleosides, [5'-13C]ribonucleosides, 7'-deoxy[5'-13C]ribonucleosides, 2'-deoxy[4-15N]cytidine, [4-15N]cytidine, 2'deoxy[6-15N]adenosine, and [6-15N]adenosine were developed more efficiently than ever; some oligodeoxyribonucleotides were constructed by the use of these materials and found to be extraordinarily feasible for the NMR spectroscopic studies. 2) A novel approach to oligonucleotide systhesis on CPG has been established by the use of a base-labile protecting group, i.e., 2-(levulinyloxymethyl)-5-nitrobenzoyl (LMNBz) protecting group for the 5'-hydroxyl group of nucleoside 3'-phosphoramidites.
During the course of a search for biologically active constituents from unexamined plant sources, several biogenetically interesting new di- and tri-terpenes and steroids were isolated from several weeds and shrubs of Euphorbiaceae and the bark, leaves and cones of several Pinaceae trees which had been treated as wastes in the forestry industry. Euphorbia supina contained 3, 4-seco-5α- and 5β-adian-4(23)-ene-3, 5-diols and related oxides, oxygenated fern-8-en-3β-ols named supinenolones A-E and unusually migrated oxyfernanes having (9S)- and (9R)-7(8→9)abeo-9-D : C-friedo-B' : A'-neogammacerane skeletons named spirosupinane and neospirosupinane, while E. chamaesyce contained 3, 4-seco-oleana-4(23), 18-dien-3-oic acid, 3, 4-seco-8βH-ferna-4(23), 9(11)-dien-3-oic acid and two oxygenated obtusifoliols. The bark of Phyllanthus flexuosus (Euphorbiaceae) containd 11β-hydroxy-D : A-friedo-olean-1-en-3-one, lup-20(29)-ene-3β, 15α-diol, olean-12-ene-3β, 15α-diol and olean-12-ene-3β, 15α, 24-triol together with trichadenic acid B for which we revised the structure to 3β-hydroxy-D : A-friedo-oleanan-27-oic acid. Two 26-nor-D : A-friedo-olean-14-enes were isolated from P. watsonii. Regarding Pinaceae trees, an unusually migrated abieslactone [(3R, 7S, 9R, 23R)-7-hydroxy-3-methoxy-8-oxo-7(8→9)abeo-lanost-24-eno-26, 23-lactone], named spiroveitchionolide, was isolated from the bark of Abies species, besides nine abieslactone analogues. Two pairs of unusually migrated serratanes, piceanonols A and B and jezananals A and B having novel skeletal systems of 14(13→12)abeo- and 16(15→14)abeo-serratanes named piceanane and jezanane, respectively, were also isolated from the stem bark of Picea species, besides three 14β, 15β-epoxyserratanes and two 13α, 14α-epoxyserratanes. The leaves of Larix kaempferi contained two deformed abietanes named karamatsuic acid (9, 10-seco-9, 10α-epoxyabieta-8, 11, 13-trien-18-oic acid) and larikaempferic acid [9α, 13α-epoxy-8-oxo-9(8→7)abeo-7β-abietan-18-oic acid], as well as the cones to contain 8α, 12α-epidioxy-15-hydroxyabiet-13-en-18-oic acid, three diepoxyabietan-18-oic acids and two new dehydroabietic acid analogues. Several of the above compounds exhibited inhibitory effects against tumorpromoting and DNA topoisomerase II activities.
The alkaloidal components of eight Erythrina plants (Leguminosae), E. arborescence Roxb., E. orientalis (L.) MURR, E. crysta-galli LINN, E. crysta-galli (L.) cv. Maruba Deiko H. Murata, E. x bidwilli LINDL, E. poeppigiana (Walp) O. F. Cook, E. glauca WILLD, and E. variegata L. were examined. As a result of this study, five new oxo-erythrinan alkaloids, erythrinine (8), 11-hydroxyerysotrine (9), erysotramidine (10), erytharbine (11), crystamidine (12) and a dibenz[d, f]azonine type alkaloid, erybidine (2), were isolated respectively. Two tetrahydroprotoberberine type alkaloids, scoulerine (4) and coreximine (5), were also isolated from E. orientalis (L.)MURR. A new synthetic route to erythrinan alkaloids was developed, via the cis -C/D-ring fused 15-methoxy-16-hydroxyerythrinan-2, 8-dione (49) as a key intermediate, from the enol methyl derivative (48) which was obtained by Birch reduction of the benzyl amide (47). The total synthesis of (±)-erysotramidine (10), an oxo-erythrinan alkaloid, including a novel ring cleavage of the azatricyclo[22.214.171.124] compound (70) with phenylselenyl chloride is described.
This review deals with the development of efficient methods to construct the basic structure of natural products and the versatile methods to control the stereochemistry, and these methods were applied to the synthesis of natural compounds. The photochemical spirodienone formation reaction was applied to the synthesis of proaporphine alkaloids. The alternative spirodienone formation reactions by the metal-catalyzed degradation reaction of phenolic α-diazoketones were applied to many natural spirocyclic compounds, such as chamigrane type sesquiterpenes, spirovetivane type phytoalexins, marine natural products, and so on. Lewis acid mediated spirocyclization reaction of cyclohexene bis-acetal derivative was developed, and this reaction was applied to the synthesis of aphidicolane and stemodane diterpenes. The regioselective cleavage reaction of the cyclopropane ring of tricyclooctanone derivatives was used for the syntheses of diquinane and triquinane compounds. A chiral pool synthesis of several aromadendrane sesquiterpenes was achieved via common tricyclic enone intermediates. The synthesis of macrocarpals, coupling products of aromadendrane skeleton and isopentylphloroglucinol dialdehyde, was also accomplished for the first time using an arene Cr(CO)3 complex as a chiral benzyl cation equivalent. The Fe(diene)(CO)3 complexes were used for the highly stereoselective asymmetric synthesis of several natural products, such as insect pheromones and alkaloid, as a versatile mobile chiral auxiliary.
We were interested in RCS (rabbit aorta contracting substance) and SRS-A(slow reacting substance of anaphylaxis) and their involvement in human bronchial asthma. When we started our anti-asthmatic drug research in the 1970's. We synthesized a lot of chemical compounds and eventually discovered that AA-861 inhibited the generation of SRS-A from the lung tissue of actively sensitized guinea pigs. AA-861 was found to be a potent 5-lipoxygenase inhibitor. This compound reduced experimental allergic asthma in guinea pigs, but it is easily metabolized in the body. More recently, we found a novel compound, AA-2414 (seratrodast), which is not metabolized in the body. AA-2414 proved to be not a 5-lipoxygenase inhibitor, but a thromboxane A2 (TXA2) receptor antagonist. Seratrodast is the first receptor antagonist that is being developed as an anti-asthmatic drug. Seratrodast inhibits both immediate-, late asthmatic responses in guinea pigs, and also reduces airway hyperresponsiveness in dogs. The anti-asthmatic action of seratrodast in animal models indicates that the drug should be of use in the treatment of human asthmatics. In clinical studies, seratrodast showed a marked effect to improve clinical parameters in bronchial asthma. It is also reported that seratrodast is free from harmful aftereffects. Clinical trials are under way in the US.
There are few reports about marker substances for the identification of Astragali Radix in formulations. First, constituents analysis was performed by HPLC for the screening of a marker substance, using several lots of Astragali Radix and its fluid extracts. As a result of the analysis, one of the main components was clearly detected even in the fluid extracts, and thought to be a good marker substance. This component was identified to be calycosin (7, 3'-dihydroxy-4'-methoxyisoflavone) by the structural analysis. Then, the identification methods of Astragali Radix and its fluid extracts in formulations were investigated with an Astragali Radix extract as a reference standard solution and calycosin as a marker substance. This method was applied to three different kinds of Kampo formulations and three different kinds of drinkable preparations. Consequently, calycosin was clearly detected by a HPLC-multi wavelength detector system, in all investigated formulations. Calycosin will be successfully used as a marker substance for the identification of Astragali Radix and its fluid extracts in formulations.
A recombinant human basic fibroblast growth factor CS23 mutein (rhbFGF-CS23) obtained from Escherichia coli cells has proliferation-stimulating activity for a fetal bovine heart endothelial cell line, ATCC CRL 1395 (biological activity), and strong affinity for heparin (heparin-affinity) similarly to the natural human basic fibroblast growth factor. Plural species having different kinds of heparin-affinity were formed by acetylation of rhbFGF-CS23 with acetic anhydride. To clarify the relationship between the sites with heparin-affinity and the biologically active sites, we have investigated the acetylation sites by peptide mapping and the biological activity of the acetylated species. Consequently, the sites with heparin-affinity in rhbFGF-CS23 are found to be Lys26, Lys119, Lys125, Lys129, and Lys135, in the primary structure, and these sites with heparin-affinity except Lys26 are also clarified to be very important to retain the biological activity of the factor.
Stabilities of chloral hydrate in an aqueous solution and its medicated syrup were examined by high performance capillary electrophoresis. Analysis of the concentration of chloral hydrate indicated that there was no obvious change in the concentration of chloral hydrate boty in the aqueous solution and in the syrup preparation after keeping them for 3 months at room temperature or at 60°C. The lowering of pH was more obvious in the syrup solution than in the aqueous solution, and this tendency was estimated to be due to the formation of hydrochloric acid. We propose that the stabilities of the preparation of chloralhydrate should be monitored by observing pH changes.