Since the discovery of the right-handed double helical structure of deoxyribonucleic acid by Watson and Crick in 1953, many pieces of detailed nucleic acid structural information involving ribonucleic acid have been elucidated and this review describes the results of the X-ray structural studies of nucleic acids and their constituents carried out in my laboratory. In the latter half the nucleic acid-protein interaction mechanism was also discussed on the basis of the molecular model of the stacking interaction between base and aromatic amino acid side chains. The structure-function relationship of ribonuclease T1·guanosine monophosphate complex was used as an example.
Two new secoiridoid glucosides, named ibotalactone A and ibotalactone B, have been isolated together with oleonuezhenide from the leaves of Ligustrum obtusifolium SIEB. et ZUCC., and the structures were elucidated on the basis of nuclear magnetic resonance spectra and other physicochemical evidence.
4-Chlorothieno [2, 3-d] pyrimidines were prepared by the chlorination of 4-oxo-3, 4-dihydrothieno [2, 3-d] pyrimidines with phosphoryl chloride. 4-Oxo-3, 4, 5, 6, 7, 8-hexahydro -benzo- and 4-oxo-6-phenylthieno [2, 3-d] pyrimidine were synthesized by the cyclization of 2-acylaminothiophene-3-carboxamide derivatives with base. 2-Methyl-4-oxo-3, 4-dihydrothieno [2, 3-d] pyrimidine was prepared by the treatment of 2-methyl-4-trichloromethylthieno [2, 3-d] pyrimidine with sodium hydroxide in aqueous methanol. A series of 4-alkylamino-and 4-arylaminothieno [2, 3-d] pyrimidines were synthesized by the nucleophilic substitution of 4-chlorothieno [2, 3-d] pyrimidines with various amines. These compounds were evaluated for antifungal activity against Piricularia oryzae. The preventive effects on Rice blast, Sheath blight, and Cucumber powdery mildew were also determined by pot tests.
A new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413), was orally administered to guinea pigs at a dose of 2 mg/kg. The drug levels in the plasma measured by the radioreceptor assay (RRA) method were significantly higher by 7% than those by the gas chromatographic (GC) method which was selective for the intact drug. Among the metabolites of KG-2413, 1-(2-ethoxyethyl)-2-(hexahydro-1H-1, 4-diazepin-1-yl)-1H-benzimidazole (desmethyl metabolite) and 1-(2-ethoxyethyl)-5-hydroxy-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole (5-hydroxy metabolite) had relatively high cross-reactivities of 29% and 21%, respectively, on the RRA method. However, the 5-hydroxy metabolite was not extracted with benzene under strongly basic conditions on the extraction procedure carried out prior to the receptor assay. Therefore, it was suggested that the desmethyl metabolite might affect the RRA method. In order to determine the amount of the desmethyl metabolite in the plasma, a high-performance liquid chromatographic method was established to determine the dansyl derivative of the desmethyl metabolite. By using this method, it was found that the desmethyl metabolite corresponding to 21-32% of the intact drug was present in the plasma after oral administration of KG-2413 at a dose of 2 mg/kg. Taking account of the cross-reactivity (29%) and extraction ratio (83%) of the desmethyl metabolite, this active metabolite affects the RRA method to give 5.1-7.7% overestimation of the intact drug concentration. Therefore, it became clear that the presence of the active desmethyl metabolite resulted in the difference between the GC and RRA method.
The tablet hardness was measured for the direct compressed tablets containing various glassbeads and binders. Intact, trimethylsilylated and chloromethyldimethylsilylated glassbeads were used to investigate the effects of surface property on the tablet hardness. The tablet hardness was decreased by the hydrophobic modification of glassbeads surface. The increase of moisture contents of binder accelerated the decrease of tablet hardness of trimethylsilylated glassbeads tablets. From the observation of scanning electron microscopy, it was concluded that the decrease of tablet hardness observed for the hydrophobic glassbeads could be explained in terms of the variation of the adhesive ability of binder particles to glassbeads.
Choleretic effects of 60 kinds of Chinese traditional medicine frequently used in clinical practice were investigated. Consequently, significant effects of choleretics were found in the methanol extracts of Ko-so-san, Intinko-to, Saiko-seikan-to, Hange-koboku-to, Antyu-san, Syo-kankyo-to, Keisi-syakuyaku-timo-to, Senkan-meimoku-to, Bohu-tusyo-san, Juzen-taiho-to, Jumi-haidoku-to Kami-syoyo-san and Hange-syasin-to. Water extracts of these Chinese traditional medicine had no such effect. Alteration of excretion of various biliary components after administration of the methanol extracts with the choleretic effect was examined, and with all medicines, bile acid excretion decreased and sodium and potassium excretions increased. Therefore, a medicine inducing choleresis involves some selective increases in the bile acid-independent fraction of bile flow. And after administration of methanol extracts of Keisi-syakuyaku-timo-to and Bofu-tusyo-san, lithogenic index, an index of saturation level of cholesterol, decreased significantly. Therefore, with these medicines, a dissolving effect on cholesterol gallstone is expected.
A new phenol glucoside, named ibotanolide B, was isolated together with de-p-coumaroylibotanolide from the leaves of Ligustrum obtusifolium SIEB. et ZUCC., and the structure was elucidated on the basis physicochemical evidence.
Intravenous and oral administrations of ethenzamide (EZ) were carried out in the rabbit, and elimination process pharmacokinetically discussed. When the drug dose increased, plasma clearance and extent of bioavailability were reduced and plasma peak times delayed after oral dosing of EZ. Michaelis-Menten type elimination parameters were estimated from the plasma concentration-time profiles after intravenous dosing of EZ. The first-order absorption rate constant (ka), hepatic available fraction (FH) and approximate elimination rate constant (K) for hepatic first-pass metabolism of EZ were estimated using computer multi-lines fitting technique by iterative nonlinear least squares regression program, MULTI (RUNGE).