The present article describes our recent synthetic studies on various biologically active compounds, including synthesis and biological properties of prostacyclins, synthetic approach toward thromboxanes, and total syntheses of coriolin and hirsutic acid C. In the final part of this review, some new reactions, exploited in connection with synthetic studies on prostacyclins, are also described.
Membrane potentials and membrane permeability coefficients of bovine eye-lens capsule and cellulose membrane were measured for L-phenylephrine HCl (mydriatic), its related compounds [DL-phenylpropanolamine HCl, and phenethylamine HCl] as well as pilocarpine HCl (myotic) and sodium chloride. It has been found that there is fairly strong interaction between phenylephrine cation and capsule, and also that pilocarpine HCl makes capsule more porous, so that its permeability coefficient across the capsule becomes large compared to other substances.
Hydrolysis of lecithin by phospholipase D at the mixed micelle surfaces composed of L-α-dipalmitoyl (DPPC) or dimyristoyl phosphatidylcholine (DMPC) and heptaethyleneglycol dodecylether (C12-E7) was investigated. The interfacial reaction was analyzed by measuring the fluorescence change of 8-anilino-1-naphthalenesulfate (ANS) present in the micelle solution. As the result, it was observed that, with increasing initial mol fraction of lecithin, XOPC, the rate constant of the enzymatic process decreased, and that an initial slow reaction occured in the mixed micelle solution with large initial mol fraction of lecithin. The rate constant decreased at higher temperature than cloud points of the mixed micelles. On the basis of these results, the interaction between phospholipase D and mixed micelles at the interface and difference of the reactivity due to the variation of the state of lecithin were discussed.
In the course of the search for anti-inflammatory constituents in the plant origin by using the fertile egg method, some Acer plants (Aceraceae) were found to have the activity. Exploration of Acer crataegifolium SIEB. et ZUCC., an active species, resulted in the isolation of 2, 6-dimethoxy-p-benzoquinone (1) as an active component. This compound (1) administered orally to intact rats at a dose of 50 mg/kg exhibited an inhibitory activity against granulation tissue formation induced by the subcutaneous implantation of cotton pellet.
The Ginseng Radix (ginseng root) is prescribed in many Chinese medicines as a stomachic and for the purpose of antidiarrhoic effect, metabolic promotion, and hematic effects, and has been well known as one of the representative drugs of nutritious tonics. In a continuing scientific search for Chinese medicines, we tried systematic extraction of some Chinese medicines, and checked activity of each fraction by means of the fertile egg method, and found a strong inhibitory activity against the formation of granulation tissue in the chloroform extract. The detailed investigation of this extract resulted in the isolation of panaxynol (1) and linoleic acid (2), which were proved to be major active components.
Three C-glucosylxanthones, 1-hydroxy-3, 5, 6-trimethoxyxanthone-2-C-glucoside (8), 1, 3, 5, 6-tetrahydroxyxanthone-2-C-glucoside (9) and isomangiferin (10), were isolated from the underground parts of Iris florentina L., besides mangiferin (2) and irisxanthone (3) which have been known as the components of this plant. In order to study the biosynthesis of 9 and 3, maclurin-(carbonyl-14C) (11) was fed to I. florentina L. Labelled 11 was efficiently incorporated not only into 2 but also 9 and 3, and the radioactivity in 9 was largely localized in the aglycone moiety. These results indicate that 11 was incorporated into 9 without randomization and that 9 and 3, therefore, were biosynthesized via C-glucosylation of maclurin (11). In addition to C-glucosylxanthones, two acetophenones, piceol (6) and acetovanillone (7), were isolated together with sinapic acid and protocatechuic acid.
Investigations were performed on the effect of peptidic antibiotics such as thiopeptin and bicyclomycin on ureolysis in rat. Neither drug inhibited urease activity of ileumcaecum contents. Thiopeptin (46 mg/kg/d) or bicyclomycin (100 mg/kg/d) was orally administered to rats two days before the measurement of 14C-ureolysis : the percentage of recovery of radioactivity expired into the breathing air was assayed (in vivo measurement). The depression percentages with thiopeptin and bicyclomycin were 59 and 35%, respectively. Urease activities of ileum-caecum contents of rats (in vitro measurement) 4 days after the treatment with thiopeptin and bicyclomycin decreased to 7 and 60% of the control rats, respectively. When being fed with thiofeed containing 100 ppm thiopeptin (10 mg thiopeptin/kg/d) for ten days, urease activity (in vitro measurement) decreased to 50-65%, but feeding of bicyclofeed containing 1000 ppm bicyclomycin (100 mg bicyclomycin/kg/d) was not effective. Susceptibility of 24 strains of intestinal bacteria to these antibiotics was examined. Thiopeptin inhibited strongly the growth of Eubacterium lentum and Eubacterium aerofaciens (MIC were 23 and 26.6 ng/ml, respectively), which were known to be urease-producing bacteria. The growth of other ureasenegative bacteria was also inhibited by thiopeptin in the similar concentrations. These results suggested that the intestinal flora were markedly affected by the antibiotics, resulting in the depression of ureolysis in vivo and decrease of urease activity of ileumcaecum contents. Bicyclomycin did not affect the growth of test bacteria at all.
Efflux of intracellular K+ from human erythrocytes was stimulated under nonhemolytic conditions by each of four phenothiazine derivatives, two non-steroidal anti-inflammatory drugs and a local anesthetic, and was dependent on time and temperature, while membrane shape change induced by them was independent of time and temperature. Cepharanthine, one of biscoclaurine alkaloids, and lipid bilayer perturbing agents, such as lysolecithin, phospholipase A2 and C, and quarternary ammonium compounds, induced membrane shape change without stimulating K+ efflux at any temperature. In contrast, N-ethylmaleimide, membrane protein modifying reagent, remarkably stimulated K+ efflux time- and temperature-dependently without inducing membrane shape change. These results suggest that the K+ efflux may result from drug-induced rearrangement of a certain membrane protein (e.g. K+-channel protein) and is independent of membrane shape change, which appears to result from the perturbation of membrane lipid bilayer.
Effect of protoporphyrin on the membrane of human erythrocytes was investigated by measuring the shape change and osmotic hemolysis. Protoporphyrin induced crenation on human erythrocyte membrane dose-dependently and the maximal effect was observed within 5 min of incubation under the conditions used. The effect on hypotonic hemolysis of the cells was biphasic ; protection of hemolysis at lower concentrations and stimulation at higher concentrations. The crenation induced by protoporphyrin was reversed to normal biconcave shape by washing the cells with albumin solution, but not with isotonic saline. Furthermore, the protoporphyrin-induced crenation was antagonized by the action of phospholipase C which by itself converted normal biconcave erythrocytes into invaginated cells due to the hydrolysis of phosphatidylcholine in the membrane. These membrane-acting behaviors of protoporphyrin are similar to those of lysolecithin and phospholipase A2, known reagents causing disturbance of membrane lipid bilayer. Thus, protoporphyrin induces the rearrangement of lipid bilayer in erythrocyte membrane which might cause disturbance of the membrane-related functions of the cells.
There are two types of water of crystallization in the crystallive state of berberine chloride. This fact was confirmed by the measurements of dielectric and thermal behaviors in the processes of adsorption and desorption isotherms. The anhydrous berberine chloride was very hygroscopic, absorbed moisture immediately, and was transformed to dihydrate even at low relative humidity. On the other hand, dihydrate was not so hygroscopic but it was transformed to tetrahydrate at relatively high humidity. The dihydrate has low values of apparent dielectric constant and apparent dielectric loss, but the tetra-hydrate showed dielectric dispersion at low frequencies. The tetrahydrate has two endothermal peaks in the desorption process of thermal analysis. The activation energies of the two peaks were small values of 12.6 and 15.9 kcal/mol, respectively. It means that the two kinds of water of crystallization in berberine chloride are not stable for the change of temperature.
Photodegradation of nifedipine tablets was studied. In order to prevent nifedipine from photodegradation by package film, the sample tablets were covered with various transparent polyethylene colored films or opaque gelatin films. They were exposed to a 20-watt fluorescent-lamp, mounted approximately 53 cm above the samples for 10 days or more. Photolysis of nifedipine without film or oovered with transparent polyethylene film containing UV absorber was very rapid. However, the colored or gelatin films could prevent the decomposition of nifedipine a little. Especially the red film, which did not transmit the light below 580 nm, prevented perfectly the decomposition of nifedipine for 28 days. The effect of wavelength of light on the photolysis was examined by using a grating monochrometer. It was found that the nifedipine tablet was sensitive to light over the range of wavelength between 340 nm and 560 nm, especially 420 nm. Relationship between protective effect on photolysis of colored or gelatin films and their transmission curves between 340 nm and 560 nm was discussed.
N-Alkylaminoephedrines (IIIa-d) having methyl, ethyl, isopropyl, and benzyl groups were synthesized by the hydrogenation of N-(alkylideneamino)-ephedrines by using lithium aluminium hydride in ether, and obtained as hydrochlorides. These hydrochlorides did not exhibit any significant activity on the bronchial musculature.
From the root of Coix lachryma-jobi L. (Gramineae), three compounds, 6-methoxy-benzoxazolinone (1), 2-hydroxy-7-methoxy-1, 4 (2H)-benzoxazin-3-one (2), and 2-O-glucosyl-7-methoxy-1, 4 (2H)-benzoxazin-3-one (3) were isolated.
The photo-stability of theophylline in aqueous solutions containing methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, propylenediamine, 1, 3-propanediamine, 1, 4-butanediamine, monoethanolamine, diethanolamine, isopropanolamine and choline under oxygen was investigated. Theophylline was photo-decomposed significantly in the presence of dimethylamine, diethylamine, ethylenediamine and propylenediamine.
To examine their properties as fluorescent labeling reagents for carboxylic acids, 2-dansylaminoethanol (III), 3-dansylamino-1-propanol (IV), 2-dansylethanol (V) and 3-dansyl-1-propanol (VI) were prepared. The reaction of III with benzoic acid in the presence of diethyl azodicarboxylate (DAD) and triphenylphosphine (TPP) in tetrahydrofuran at room temperature for 30 minutes gave 2-dansylaminoethyl benzoate (VIIa ; 57%) and N-dansylaziridine (VIIb ; 41%), whereas IV gave exclusively the ester, 3-dansylamino-1-propyl benzoate (VIIIa ; 90%). III and IV with DAD and TPP in the absence of benzoic acid were converted into VIIb (76%) and N-dansylazetidine (VIIIb ; 64%), respectively, as a result of cyclodehydration. No esters were obtained from V and VI with benzoic acid under similar conditions, and their reactions resulted in dansyl-ethylene (IX ; 64%) and recovered VI, respectively.