The auther has developed numerous new reactions utilizing sulfur-containing leaving groups and attempted to use them for the synthesis of biologically active natural products. As shown in Chart 2, the mode of elimination of the sulfur-containing leaving groups is classified into two types. In the first half of this review, a type 2 reaction, in which 3-acyl-1, 3-thiazolidine-2-thione is used as Y-[○!S]and an amine as the nucleophile, is outlined. In the latter half, its application is described. It is concerned with the total synthesis of macrocyclic spermidine alkaloids (codonocarpine, (±)-lunarine, and (±)-lunaridine), the peptide synthesis, the total synthesis of parabactin, a spermidine-containing siderophore, the synthesis of new hypoxic cell sensitizers, FNT-1 and FNT-2, and a new design for chiral induction to the prochiral a cyclic molecules.
Characteristics of the phase transition exhibited by a hypoglycemic agent DG-5128 (a cyclic guanidine derivative) were examined by differential thermal analysis (DTA) and thermogravimetry (TG). Consequently, the phase transition and its physicochemical mechanism were elucidated as follows. (1) The phase transition of DG-5128 was attributed to the dissolution process of DG-5128 anhydride into free water which was generated from the water of crystallization contained in itself by thermal conversion. (2) The dehydration reaction was a three-dimensional diffusion process following Jander's equation, with an activation energy of 66.3 kcal/mol. In addition, the meaning of crystal or amorphous of DG-5128 anhydride produced from DG-5128 under dehydration conditions, was discussed in relation to the mechanism of the dehydration process.
From Lycopodium phlegmaria L. collected in Sri Lanka, seven new alkaloids together with two known alkaloids, lycoflexine (2) and fawcettidine (5), have been isolated. Among seven new alkaloids, the structures of six alkaloids, N, N'-dimethylphlegmarine, 8-deoxyserratinidine, lycophlegmarine, epidihydrofawcettidine, lycophlegmine, and 8-deoxy-13-dehydroserratinine, were determined as shown by the formulas, 3, 4, 6, 8, 9, and 11, respectively.
In non-aqueous titration, some indicators have no simple color change but pass successively through a wide range of the color shades. Dull color change of the indicator introduces a large indicator error at the end point of the titration. To ensure accuracy, the chemical stoichiometric relationship between color transition of the indicator and the equivalence point was considered. The color transition of the indicator was calculated by simplified complementary tristimulus colorimetry (simplified CTS method) in which the steps for reading absorbance in the three ranges of absorption spectra were simplified. The calculation of the color transition made us possible to derive the theoretical equation for the determination without indicator error. In a visual titration by using an indicator, the color shade at the end point of non-aqueous titration had been decided empirically without theoretical treatise. Then by using the simplified CTS method, the color shade at the equivalence point of the titration could be known previously from the theoretical relationship between the titration ratio and the concentration of free titrant. As a typical example of these sujects, 3 ml of 10-2M glycine was titrated with α-naphtholbenzein as an indicator and perchloric acid as a titrant in anhydrous acetic acid. (Recovery : 97.3%)
A glycoprotein was extracted from Chlorella vulgaris BEYERINCK and purified by gel filtration on Sephadex G-150. Its molecular weight was 1.21×105 and the composition ratio of sugar and protein was 1 : 1 (w/w). The content of α-helical structure was determined as 18.9% by CD. It was found to have an antitumor activity against sarcoma 180 implanted in mice and also against mouse lymphemia L-1210/v/c in culture.
The binding of 1, 1'-ethylene-bis (1-nitrosourea) (EBNU), 1-methyl-1-nitrosourea (MNU), and 1-ethyl-1-nitrosourea (ENU), labeled their alkyl groups with 14C, to rat liver chromatin was compared in vitro. The alkylating activity to chromatin decreased in the order of MNU, EBNU, and ENU. The effects of nine N-nitrosoureas (three bis-N-nitrosoureas, five mono-N-nitrosoureas, and chloroethyl-N-nitrosourea) on the template activity of rat liver chromatin and E. coli DNA were compared by using exogenous bacterial DNA-dependent RNA polymerase system. The inhibition on the template activity of rat liver chromatin was dependent on the concentration of EBNU and on the time course of alkylation in the case of MNU and EBNU. The template activity was inhibited by EBNU, 1, 1'-propylene-bis (1-nitrosourea), MNU, ENU, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The inhibitory effects had a tendency to decrease with increasing the length of alkyl chain. The inhibitory effects to E. coli DNA were stronger than those to rat liver chromatin. The template activity of rat liver chromatin was slightly increased by 1, 1'-hexamethylene-bis (1-nitrosourea), 1-isobutyl-1-nitrosourea, and potassium cyanate.
The kinetic isotope effects in the metabolism of paeonol (2-hydroxy-4-methoxy-acetophenone ; I) labeled with stable isotopes, 2-hydroxy-4-methoxy [d3] acetophenone (I-d3) and 2-hydroxy-4-methoxy [d3] acetophenone [acetyl-13C2] (I-13C2d3), were investigated. In order to evaluate the effect of deuterium labeling on the metabolic rate of I, an equimolar mixture of I and I-13C2d3 (I : I-13C2d3), or I and I-d3 (I : I-d3) was orally administered to man, rabbits, guinea pigs, rats and mice. Urinary metabolites were purified by extraction with ether and by thin-layer chromatography, then subjected to gas chromatograph-mass spectrometer after acetylation. The I-metabolites were measured by using selected ion monitoring focused on their [M-COCH2]+ or [M-2COCH2]+ ions. The kinetic isotope effect was estimated from the ratio of the amount of the metabolite excreted from stable-isotopically labeled I to that excreted from I (L/UL ratio). After the administration of I : I-13C2d3, L/UL ratios of unchanged metabolites were in the range of 0.97 to 1.06. That is, no difference of the excretion rate between the labeled and unlabeled compounds was observed. On the contrary, L/UL ratios of 4-demethyl metabolites were in the range of 0.20 to 0.38. These values indicate that the amount of labeled metabolite is less than that of unlabeled one. Though a remarkable isotope effect was also observed in the case of 5-hydroxy metabolites, the amount of unlabeled metabolite was less than that of labeled one. After the administration of I : I-d3 to man and rats, the same isotope effect as in the case of I : I-13C2d3 was observed. It is suggested from these facts that the kinetic isotope effect observed in the metabolism of I : I-13C2d3 is "Metabolic switching"due to deuteromethoxy group of I-13C2d3.
By use of X-ray diffractometry, thermal analysis and infrared spectroscopy, the crystal forms of N-(2, 6-dimethylphenyl)-Δ8-dihydroabietamide were investigated. Two polymorphic forms (form I and II), two solvates (cyclohexane and CCl4), and an amorphous form were identified. Heating of form II induced a solid transformation to form I. The transition of form I and II to the amorphous form was observed by grinding. Each solvate contained 9.0% cyclohexane and 16.0% CCl4 respectively, i.e., drug : solvent=2 : 1. The activation energy of the desolvation was determined from TG curves by using Ozawa's method, and calculated as 72.2 kcal/mol for the cyclohexar solvente, and 35.5 kcal/mol for the CCl4 solvate.
The presence of three kinds of hydrates of AM-715 (1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid) was confirmed by elemental analysis, Karl-Fischer method, thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy, and X-ray diffractometry. Anhydrous AM-715 was not hygroscopic under less than 36% of relative humidity, but easily transformed to 5/2-hydrate over 62-78% of relative humidity and 5-hydrate above 94% of relative humidity, at 40°C. Anhydrous AM-715 was transformed to 5/2-hydrate with the first-order kinetics and 5/2-hydrate was dehydrated according to the first-order kinetics with an activation energy of dehydration of 22 kcal/mol. The 5/2-hydrate was converted to 5-hydrate much slowly than anhydrous AM-715. Dissolution rates were determined in water by using tape procedure, showing a slight difference between anhydrous AM-715 and its hydrates. In order to determine the effect of hydration on bioavailability, the serum levels in dogs were measured after oral administration. There were no significant differences among bioavailability of anhydrous AM-715, its 5/2-hydrate and 5-hydrate.
The behavior such as absorption and stability in gastrointestinal tract and the biliary excretion of acemetacin were examined in rats, and compared with those of indomethacin. Acemetacin was absorbed quickly from gastric and intestinal loops. The formation of indomethacin from acemetacin during the permeation across the gastrointestinal tract was small. From the results by using the homogenates of liver, it was assumed that the liver was a main part for the formation of indomethacin. After the intraduodenal administration of acemetacin, unconjugated indomethacin and desmethylindomethacin glucuronide were excreted in 0-24 bile as major metabolites. When indomethacin was administered, conjugated indomethacin was also excreted in bile. Enterohepatic circulation of indomethacin was observed after the administration of acemetacin and indomethacin.
The photosensitized oxidation of theophylline in aqueous solutions containing methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, propylenediamine, 1, 3-propanediamine, 1, 4-butanediamine, monoethanolamine, diethanolamine, triethanolamine, isopropanolamine and choline was investigated. When a solution of theophylline and Rose Bengal in aqueous ethylenediamine was irradiated with a 100 W high-pressure mercury lamp under bubbling oxygen, theophylline was decomposed to yield an unstable photo-oxidation product A. Treatment of A with 1 N NaOH produced 1, 3-dimethylallantoin and ethylenediamine, while treatment of A with 1 N HCl produced 1, 3-dimethyllumazine. When the other amines were used, theophylline gave 1, 3-dimethylallantoin as a main product.
An antifungal compound was isolated from the dried Shiitake (Lentinus edodes). The chemical structure is shown to be bis [(methylsulfonyl) methyl] disulfide on the basis of its spectroscopic data. This compound showed a potent antifungal activity against Trichophyton sp.
Droplet current distribution technique by using an aqueous stationary phase and immiscible organic solvent as a mobile phase was examined to improve the common separation procedure which has been carried out by a batch process. Control of pH and the addition of salts in the aqueous stationary phase were found to be useful for the effective isolation of the model compound with flow manipulations employing the minimum amount of solvent.
Cardiovascular effects of pennogenin tetraglycoside (Tg) extracted from Paris quadrifolia LINN. were investigated in mice, bull-frogs and rabbits. The Tg doses of 1-10 mg/kg (i.v.) produced a fall in blood pressure. The fall in blood pressure was not affected by the pretreatment with atropine and physostigmine. On the isolated bull-frog heart preparation in Yagi-Hartung's method, Tg caused a marked increase in the amplitude without changes in the heart rate at a concentration of 3.3×10-6 g/ml. At a concentration of 3.3×10-5 g/ml, Tg caused a slight increase in the amplitude with a marked augmentation in the tonus. On the cardiograph method in rabbits', Tg at a dose of 0.5 mg/kg (i.v.) produced a fall in blood pressure, an increase in the amplitude and tonus in the heart and an inhibition in respiration. These results suggest that Tg has a stimulating action on cardiac system.
From the root of Talinum paniculatum GAERTNER (Portulacaceae), a mixed compound of 1-hexacosanol, 1-octacosanol and 1-triacontanol, its acetate, and a mixed compound of campesterol, stigmasterol and β-sitosterol together with β-sitosteryl-β-D-glucoside were identified.