A procedure has been devised whereby out of a pair of 2'-5'-and 3'-5'-positional isomers of 2-thiouridylyl- and uridylyluridine derivatives, the former could be selectively cleaved into halves through the 2, 2'-anhydronucleoside formation so that the isolation of the dinucleoside monophosphate having natural linkage may become easier. In this connection, conditions for selective 2, 2' anhydro-bond formation have been examined and 2-(t-butoxycarbonyl) phenyl group has been introduced as a protecting group for the phosphate of dinucleoside monophosphates (e.g., 8c and 9c). A simple procedure for the synthesis of 2, 2'-(S)-anhydro-2-thiouridylyl-(3'-5')-uridine was also described.

View full abstract

Analgesic activity of ten 2-(N-substituted amino) methyl-7-methoxy-2, 3-dihydroben zofurans was examined by the acetic acid method and the Haffner tail pinching method. Some of them showed a potent analgesic activity. In order to investigate the true nature of their analgesic activity, the activity of morphine and of levallorphan combined with the test compounds were studied. None of the test compounds had any antagonistic activity against morphine and levallorphan. The analgesic activity of these compounds seems to be non-narcotic.

View full abstract

1, 2-Benzisoxazole-3-acetamidoxime hydrochloride (PF-257) was found to have a potentiating effect on the β-(3, 4-dihydroxyphenyl)-L-alanine response in addition to the imipramine-like effect on behaviors in rodents. In the present experiments, the effects on the caudate spindle and additional several responses of PF-257 were examined to clarify the mode of action of the compound on the central dopaminergic system. In gallamine-immobilized cats, PF-257 depressed the caudate spindle in a dose of 5 mg/kg, i.v. which changed the spontaneous electroencephalographic (EEG) arousal patterns to the drowsy ones and had little or no effect on the EEG arousal response induced by stimulation of the sciatic nerve. With 5 mg/kg which caused the EEG changes, PF-257 facilitated both recruiting response and cortical focal seizure elicited by stimulation of the thalamus and visual cortex, respectively. With 10 mg/kg, acceleration of the spontaneous EEG arousal patterns, facilitation of the EEG arousal response, and biphasic actions on both recruiting response and caudate spindle were observed. From these results, it seems possible to conclude that PF-257 has one of sites of action in the caudate nucleus and the depression of this nucleus by the compound probably results in the increased susceptibility of the thalamo-cortical region.

View full abstract

Free radical telomerization of vinylene carbonate with bromoform (and carbon tetrabromide) afforded two isomeric telomers, dibromomethylene-4, 4'-bis (5-bromo-1, 3-dioxolan-2-one) (5a, b) as two fold addition products in addition to the 1 : 1 adducts. On the similar treatment, this type of products (7a, b 9a, b) was obtained from 5-substituted-4-tribromomethyl-1, 3-dioxolan-2-ones. A sequence of reactions involving methanolysis and reductive photolysis to give methyl 5-methoxypyranosides permitted the stereochemical assignment of 5a and b as dl (anti)-and meso (syn)-configurations, respectively.

View full abstract

The interaction between bovine serum albumin and dodecahydrododecaborate B₁₂H₁₂^2- or mercaptoundecahydrododecaborate B₁₂H₁₁SH^2- anion has been investigated by equilibrium dialysis, equilibrium distribution in and out of a Sephadex gel, gel-filtration-, ion-exchange-, and ion-retardation-chromatographies. The results have been discussed with the following conclusions. 1) Both borates are strongly bound to the albumin through ion-pair formation with cationic sites on the protein molecules. 2) This binding of ionic character can be readily broken up by ion-exchange or ion-retardation chromatography. 3) The latter borate shows, in addition, another mode of binding which is resistant against ion-exchange and ion-retardation resins. 4) This binding of covalent character is due to the formation of disulfide linkage between the boron cage of B₁₂H₁₁SH^2- and the albumin.

View full abstract

Two models have been proposed for the reaction between mercaptoundecahydrododecaborate ions and protein molecules. Both models assume two-step reactions, the first step being different between the two models ; random- and monogamous-pairing models. Measuring the equilibrium concentrations of protein-ligand complex for many combinations of the borate and protein concentrations, and applying the modified simplex method to the data obtained, one can find out a set of parameter values by which the experimental results are best explained. These parameters include the number of active sulfhydryl groups, α, the number of active disulfide groups, β, per intact protein molecule, and the equilibrium constants, K₁ and K₂, for the first and second steps.

View full abstract

A novel guanosine analog, aminonucleoside antibiotics (2AG), produced by Enterobacter sp., was identified as 9-(2'-amino-2'-deoxy-β-D-ribofuranosyl)-guanine (2'-amino-2'-deoxyguanosine) by proton magnetic resonance and carbon-13 nuclear magnetic resonance spectra of 2AG and acetylated 2AG, and also by the comparison of the aminosugar obtained by hydrolysis of 2AG with 2-amino-2-deoxypentoses appeared in the literatures. This is the first report on the occurrence of 2-amino-2-deoxy-D-ribose in nature.

View full abstract

The distribution of drugs in blood of rat in relation to age were studied in an in vivo experimentation. The volume of erythrocyte and plasma were reversed at about the age of 60-70 days when the body weights were about 200g and this evidence was supported in the hematocrit value which exceeded 50% at this stage. It was elucidated that this reversion caused by the relative decrease in the volume of plasma fraction while the volume of erythrocyte fraction was kept almost constant at these stages of the animal. Reflecting the fluctuation in the volume of these fraction, the distribution ratio (E/P) increased with increasing in the age. Concerning the effect of dose on the E/P ratio, that the ratio increased with increasing the dose of the administered drug was demonstrated and the mechanism of this phenomena was also discussed.

View full abstract

4aH-r, 2H-cis, 2-Hydroxy-2, 3, 4, 4a-tetrahydro-8, 9-methylenedioxy-6 (5H)-phenanthridone, which was an important compound lacking two hydroxyl groups at 3-and 4-position in the structure of lycoricidine, was synthesized and configuration of the hydroxyl group was comfirmed to be α-quassi-axial on the basis of NMR data. A new lactam cyclization technique using borontrifluoride etherate on the course from phenethyl isocyanates to the corresponding lactams was examined.

View full abstract

The first total synthesis of (±)-lycoricidine and confirmation of its full structure were established. In the synthesis of a key compound, 4H-r, 1H-trans, 2H-cis, 10bH-trans, -1-(2'-tetrahydropyranyloxy)-2-hydroxy-8, 9-methylenedioxy-1, 2, 4a, 10b-tetrahydro-6 (5H)-phenanthridone (14), Sharpless's procedure for preparation of allyl alcohols from epoxides using selenophenolate and hydrogene peroxide was applied.

View full abstract

The C-13 magnetic resonance chemical shifts of quinolizidine and cis-and trans-4-methylquinolizidine were examined. The correlations between the stereochemistry of these compounds and results on their C-13 chemical shifts and protonation and quaternization effects were examined. trans-4-methylquinolizidine was concluded to have a trans-fused ring and an axial methyl proup. The C-H coupling constants of those compounds were also examined.

View full abstract

A method for the simultaneous analysis of cardiac steroids by high-pressure liquid chromatography has been developed. Reversed phase chromatography on a μ-Bondapak C₁₈ column was particularly effective for the separation of sixteen bufadienolides and nine cardenolides. Determination of the principal bufogenins in the fresh venom of the Japanese toad was carried out by the internal standard method. The relationship between chemical structures and retention values is also discussed.

View full abstract

Some 1-(N, N-disubstituted amino) pyrazoles were synthesized by 1, 3-dipolar cyclo-addition of 3-(N, N-disubstituted amino) sydnones with acetylenes. Arylacetylenes gave 3-arylpyrazoles preferentially. The structures were determined by ultraviolet and nuclear magnetic resonance spectroscopy, and further confirmed by catalytic hydrogenolysis and mass spectroscopy. Nitration and halogenation of 3-phenyl-1-aminopyrazoles occurred smoothly at C-4 first and at C-5 subsequently.

View full abstract

O-Ethyl succinimide (I) and O-ethyl 4, 4-dimethylglutarimide (II) were reacted with active methylene compounds (ethyl cyanoacetate and ethyl acetoacetate), phenylhydrazine and its derivatives, and N-bromosuccinimide. Furthermore, the salt formation of the cyanoacetylidene compound (III), the hydrolysis of the acetoacetylidene compound (VIII), the Fischer indolization of the imidrazones (XIII and XIV), and the Favorskii rearrangement of the 3-bromo-imides (XX and XXI) were examined.

View full abstract

Antituberculostatic agent ethambutol, possessing a little molar specific rotation, was converted to several metal chelated derivatives. Among them, the copper chelate showed a large ellipticity value in its circular dichroism (CD) spectrum. A quantitative analysis of ethambutol by means of the copper chelation followed by CD spectroscopic measurements were investigated. Thus, addition of 0.1 ml of 0.3% ethanolic solution of ethambutol to 2.9 ml of 0.01% ethanolic solution of cupric chloride was ready to form copper chelated ethambutol which gave CD ellipticity value 4.6±0.3 in its CD spectrum. The present method is one of the convenient procedures to introduce a chromophoric nature to an optically active amino alcohol for a CD measurement.

View full abstract

The synthetic strategy for the suppression of α to β rearrangement of aspartyl peptides during anhydrous hydrogen fluoride treatment was designed in which the carboxyl protecting groups stable to hydrogen fluoride, such as β-phenancyl or β-p-nitrobenzyl ester, were used and the protected peptides were treated with hydrogen fluoride-anisole mixture to remove protecting groups other than β-phenancyl or β-p-nitrobenzyl ester group followed by deprotection of the β-carboxyl protecting group under the mild conditions. Thus, the model dipeptide derivative, Z (OMe)-Asp (ONb)-Ser (Bzl)-OBzl, was treated with hydrogen fluoride-anisole mixture. The product was submitted to hydrogenolysis to remove the p-nitrobenzyl ester group. Under such a strategy, no product due to the rearrangement was detected on paper chromatograms. Similarly, the treatment of Boc-Asp (OPac)-Ser (Bzl)-OBzl gave a satisfactory result. H-Asp-Ser-Asp-Pro-Arg-OH, which is a fragment of immunogloblin E and is reported to be biologically active, has been synthesized from Boc-Asp (ONb)-Ser (Bzl)-Asp (ONb)-Pro-Arg (NO₂)-resin as an application of this strategy. Chemical and physical properties of the pentapeptide were in fair agreement with those of the pentapeptide which was synthesized under the mild conditions from Boc-Asp (OBzl)-Ser (Bzl)-Asp (OBzl)-Pro-Arg (NO₂)-ONb.

View full abstract

Reaction of 2-acetyl-5, 5-diphenyl-2, 4-pentadienoic acid (Ia) and its methyl ester (Ib) with diazomethane gave rise to 3-acetyl-3-methoxycarbonyl-4-(β-phenylstyryl)-1-pyrazoline (IIb), which by elimination of nitrogen afforded methyl 2-acetyl-6, 6-diphenyl-3, 5-hexadienoate (IIIb). Similar reaction of 3-(γ-phenylcinnamylidene)-2, 4-pentanedione (Ic) and dimethyl γ-phenylcinnamylidenemalonate (Id) with diazomethane gave the adduct corresponding to 1-pyrazoline derivatives (IIc, IId), respectively. Heating of these compounds afforded denitrogenated products. Similarly, methyl 2-acetyl-5-phenyl-2, 4-pentadienoate (Ie) and 3-cinnamylidene-2, 4-pentanedione (If) reacted with diazomethane, followed by elimination of nitrogen, to afford methyl 2-acetyl-6-phenyl-3, 5-hexadienoate (IIIe) and 3-(4-phenyl-1, 3-butadienyl)-2, 4-pentadione (IIIf), respectively. The reaction of the pyrazoline (II) to give compound (III) involves the novel ring-cleavage of the cyclopropane intermediate, such as methyl 1-acetyl-2-(β-phenylstyryl)-cyclopropane-1-carboxylate (IX, where R₁=phenyl, R₂=methyl, R₃=methoxy).

View full abstract

Amounts of 1-anilino-8-naphthalene sulfonate (ANS) adsorbed by whole bovine erythrocyte and by its ghost membrane were studied at ANS concentration from 0.01 to 3mM. For whole erythrocyte the amount is nearly proportional to the free ANS concentration with the ratio of 1.1×10 [mole/l-packed-erythrocyte] / [mole/l-medium]. The ghost membrane has two kinds of binding site for ANS. The dissociation constants and the numbers of binding sites are calculated as follows : K_I=9.1×10^-5M and n_I=1.9×10^-2 mole/kg-membrane for site I ; K_II=1.0×10^-2 M and n_II=5.8×10^-1 mole/kg-membrane for site II. The binding site I and II can be attributed to protein and lipid, respectively, judging from membrane mass per mole of sites. The mechanism of disk to sphere transformation was discussed from these results.

View full abstract

In order to search useful fluorescent thiol reagents, a naphthalene ring with a dimethylamino or methoxy group was selected as a fundamental fluorogenic group. On the basis of the design to combine such a fluorogenic and a maleimide group, 11 and 15 were synthesized as the candidate thiol reagents. Analogous model compounds (13 and 17) were also prepared. Their absorption and fluorescence spectra were measured, and the structural requirements for the candidate fluorogenic groups were discussed. Some of dimethylaminonaphthylmaleimides were found to be potential fluorescent thiol reagents.

View full abstract

On sequential treatment of benzylpenicillanates (1) or their sulfoxides (7) with phosphorus pentachloride, methanol, and sodium bicarbonate or dimethylaniline, 6-(dimethylphosphoramido) penicillins (5) or their sulfoxides (8) were obtained. 6-(Dimethylphosphoramido) penicillin sulfoxides (8) were rearranged thermally to their corresponding desacetoxycephalosporins (10). The dimethylphosphoryl group of 7-(dimethylphosphoramido) desacetoxycephalosporins (10) was removed by either a 85% phosphoric acid or polyphosphoric acid, which caused the degradation of β-lactam ring in 6-(dimethylphosphoramido) penicillins (5) and their sulfoxides (8). The dimethylphosphoryl group of penicillins and desacetoxycephalosporins was also removed by phosgene and pyridine to give 6-isocyanatopenicillins (16) and 7-isocyanatodesacetoxycephalosporins (15), respectively.

View full abstract

The difference between the mass spectra of Ar-CH=N-N=CH-Ar derivatives and those of Ar (OH)-CH=N-N=CH-Ar (OH) derivatives was pointed out. Mass spectra of 24 kinds of ortho-hydroxyaromatic aldehyde para-substituted benzylidenehydrazones (Ar (OH)-CH=N-N=CH-Ar'-R) were determined. These compounds were shown to have several kinds of characteristic fragment ions ; [Ar (OH)-CH=N]⁺ (gion), [N=CH-Ar'-R]⁺ (g'ion), [Ar (OH)-CH=N+H]^+·, [Ar (OH)-CH=N-H]^+·, [N=CH-Ar'-R+H]^+·, [N=CH-Ar'-R+2H]⁺ and [M-OH]⁺ (b ion). The relative ion intensities of g, g'and b ions were found to be strongly dependent on the substituent constant. And all of the values of log [g⁺] / [^dM^+·], log [g'⁺] / [^dM^+·], and log [b⁺] / [^dM⁺] were shown to correlate linearly with σ⁺. The substituent effect on the value of either log [g'⁺] / [g⁺] or log [b⁺] / [g⁺] was found to be the reflection of the substituent effect on the difference of ionization potentials of either g· and g'· radicals or g· and b· radicals, respectively.

View full abstract

The effects of pre-administered fats and fatty acids on the absorption of tryptophan from the rat small intestine were investigated using in situ recirculation and in vitro everted sac techniques. Pre-administration of octanoic acid significantly inhibited the absorption of L-tryptophan, and this effect was not rapidly reversible. Trioctanoin, oleic acid, methyl octanoate, and octyl alcohol modestly inhibited the absorption of L-tryptophan, while triolein and olive oil did not significantly affect. The maximal transport capacity (V_max) seemed to be affected rather than Michaelis constant (K_m) by the administration of octanoic acid. Pre-administration of octanoic acid also inhibited the transport of L-tryptophan in vitro. In contrast, the absorption of D-tryptophan was partially inhibited by octanoic acid. With the pre-administration of octanoic acid there was an increase in the amount of protein released into the perfusate when compared to the control or the administration of other lipids. It is possible that the effect of pre-administered octanoic acid on the intestinal absorption of tryptophan may be due to the loss of structural and/or functional integrity of the intestinal membrane.

View full abstract

Stereoisomeric alanine containing peptides were synthesized. L-Ala-L-Ala and L-Ala-Gly induced germination of Bacillus thiaminolyticus spores and L-Ala-L-Ala and Gly-D-Ala inhibited L-alanine or L-Ala-L-Ala induced germination. The relationship between the structure of alanylpeptides and the effects on germination were also studied. Antibacterial activity of synthetic alanylpeptides against gram positive and gram negative organisms was also studied.

View full abstract

A new polyoxypregnane having 5α, 6β-hydroxyl groups, glycopenupogenin (I), was isolated from Cynanchum caudatum MAX., and its structure was elucidated on the bases of physical data and chemical reactions. I was found to be identical with a derivative obtained by the glycolation of penupogenin (IV), which had been isolated from the same plant.

View full abstract

The mechanism by which dosage of carbamazepine (5H-dibenz [b, f] azepine-5-carboxamide) interferes with the Porter-Silber reaction for the determination of urinary 17-hydroxycorticosteroids has been investigated. A specimen of human urine collected following oral administration of carbamazepine was processed in the usual manner. The principal metabolites responsible for the Porter-Silber test were separated and characterized to be carbamazepine-10, 11-epoxide and dihydrocarbamazepine-10, 11-trans-diol by usual criteria. Being treated with the incomplete Porter-Silber reagent, these metabolites underwent facile rearrangement yielding acridine-9-aldehyde accompanied with a small amount of acridine. It has been disclosed that the interference in the determination of 17-hydroxycorticosteroids due to the undesirable coloration is ascribable to the formation of acridine-9-aldehyde phenylhydrazone from the drug metabolites.

View full abstract

Calcium D (+)-pantothenate crystallized from various solvents was proved to have three polymorphs (α-, β-, and γ-form), an amorphous form and a solvate which contained 4 molecules of methanol and 1 molecule of water of crystallization. It was also found that the solvate was changed to the amorphous form by drying, to α-form on standing in a closed container at temperatures above 30° and to the monohydrate on standing in atmosphere. The data of X-ray powder diffraction, infrared spectroscopy and dissolution behavior are presented for the identification of these various forms.

View full abstract

The methylations of twenty-five 1, 2, 4-triazoles with methyl iodide and diazomethane were studied and substituent effects on the product ratios are discussed. Methylation of 1, 2, 4-triazole and its symmetrically 3, 5-disubstituted derivatives occurred almost exclusively at the 1-position. These results are interpreted in terms of the α-effect of the α-diaza structures of the 1- and 2-positions in the 1, 2, 4-triazoles. Methylations of 3-substituted 1, 2, 4-triazoles with methyl iodide and diazomethane occurred preferentially at the N-1 atom, which is sterically less hindered. However, methylation of 3-α-pyridyl-1, 2, 4-triazole with diazomethane occurred preferentially at the N-2 atom next to the α-pyridyl group due to the particular space effect of the α-pyridyl group. Methylation of 3, 5-disubstituted 1, 2, 4-triazoles occurred predominantly at the vicinal nitrogen atom next to the electron-releasing group, but 3-α-pyridyl derivatives were methylated mainly at the vicinal nitrogen atom next to the α-pyridyl group.

View full abstract

Two arabinosides (designated as YM-I and YM-IV) were isolated along with their monoacetyl derivatives (YM-II and YM-III) from the less polar glycoside portion of the total glycoside mixture which was isolated from the epigeous part of Metanarthecium luteoviride MAXIM. (Liliaceae). On the basis of chemical and physicochemical evidence including the synthesis of YM-IV pentaacetate (4b) from metagenin (6), the structure of YM-I has been elucidated to be 11-O-α-L-arabinopyranosyl-3-epi-metagenin (3), while the structure of YM-IV has been established as 11-O-α-L-arabinopyranosyl-metagenin (4).

View full abstract

Various reactions usually carried out on heterocyclic N-oxides were examined on 1-methyl-(IIm-0) and 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine 5-oxide (IIp-0) prepared from the condensation-cyclization of 1-methyl-(IIIm-1) or 1-phenyl-5-amino-4-hydroxyiminomethyl-1H-pyrazole (IIIp-1) and ethyl orthoformate. The reaction of IIp-0 with alkaline solution gave the ring fission product between the 5- and 6-position such as 5-formamido- (IIIp-5) and 5-amino-4-hydroxyiminomethyl-1-phenyl-1H-pyrazole (IIIp-1). Application of the Reissert reaction to II-0 resulted in the formation of the ring fission products such as O-benzoyl derivative of IIIp-1 (IIIp-6) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (IIIm-3). Acetic anhydride and IIm-0 gave 1-methyl-1H-pyrazolo [3, 4-d] pyrimidin-4-ol-(Im-4). But the reaction with IIp-0 gave both 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine-4-ol (Ip-4) and 5-acetamido-1-phenyl-1H-pyrazole-4-carbonitrile (IIIp-8). Ip-4 was also obtained from the reaction of IIp-0 with tosyl chloride. The thermal decomposition of II-0 afforded 4, 4'-bis [1-methyl-1H-pyrazolo [3, 4-d] pyrimidine] (IXm) and 4, 4'-bis [1-phenyl-1H-pyrazolo [3, 4-d] pyrinidime] (IXp) together with 1-methyl-(Im-0) and 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine (Ip-0). The Grignard reaction of II-0 gave 1-Methyl-(IIm-7-9) and 1-phenyl-4-alkyl-1H-pyrazolo-[3, 4-d] pyrimidine 5-oxide (IIp-5-9). Im-0 and II-0 were transformed into 1-methyl-(XIXm) and 1-phenyl-1H-pyrazolo [3, 4-b] pyridines (XIXp) by the reaction with some active methylene compounds or ketone such as malononitrile (A-1), ethyl cyanoacetate (A-2), ethyl acetoacetate (A-3), acetylacetone (A-4) and cyclohexanone (A-5). Thus, in the presence of ethoxide ion Im-0 reacted with A-1 to give 6-amino-1-methyl-1H-pyrazolo [3, 4-d] pyridine-5-carbonitrile (XIXm-1). The direct reaction of IIm-0 with A-1 and A-2 gave 4, 5-dihydro-5-hydroxy-1-methyl-1H-pyrazolo [3, 4-d] pyrimidine-4-malononitrile (XXm) and ethyl α-cyano-4, 5-dihydro-5-hydroxy-1-methyl-1H-pyrazolo [3, 4-d] pyrimidine-4-acetate (XXm-2). But the direct reaction with A-3, 4 and 5 afforded the corresponding XIXm (XIXm-3, 4, and 5), respectively. The reaction of IIp-0 with A-1, 3, and 4 formed the corresponding XIXp (XIXp-1, 3, and 4) together with IXp (in the case of A-3 and 4), Ip-0 (in the case of A-4) and the ring fission product such as ethyl 2-(4-cyano-1-phenyl-1H-pyrazol-5-ylaminomethylene)-3-oxobutyrate (XXIp-3) and ethyl 2-(4-hydroxy-iminomethyl-1-phenyl-1H-pyrazol-5-ylaminomethylene)-3-oxobutyrate (XXIp-3') (in the case of (A-3).

View full abstract

Pyrimido-(1, 4)-benzothiazinedione (I) underwent oxidative coupling with water, alcohols and morpholine at the 4α-angular position in the presence of iodine and base such as triethylamine or morpholine. The facile Pummerer rearrangement of its sulfoxide also give 4α-substituted derivatives. The mechanisms of these reaction are also discussed.

View full abstract

Antimicrobial compound LA-1 (I) has been isolated from the culture broth of the leucomycin (LM) producing strain, Sm. kitasatoensis NU-23-1 and its structure determined. It has been found that the new compound I is transiently accumulated preceding the production of LM during fermentation process. I is extracted with organic solvents under acidic conditions from the culture filtrate of its highly accumulative mutant NU-4-4-2 after 27-30 hours incubation. I is exceedingly unstable in its solid state. Its ultraviolet (UV) spectrum (UV λMeOHmax nm : 270) and infrared (IR) spectrum (IR νCCl4max cm-1 : 3000-, 1925, 1700-, 1630-1610, 985) have suggested that I is an oxo-unsaturated fatty acid having a conjugated allene segment. Its proton magnetic resonance (PMR) and 13Carbon-nuclear magnetic resonance (CMR) spectra and the spectroscopic data (IR, PMR, CMR, and mass spectrum) of its stable derivatives, octahydro LA-1 (II) and octahydro methyl LA-1 (III), have been fully compatible with the molecular formula, C10H10O3 and with the molecular weight, 178. Its structure has been elucidated on the basis of these spectroscopic properties.

View full abstract

Michaelis constant, Km and relative catalytic constant, k^rel_catwere determined for the β-acetylglucosaminidase-catalyzed hydrolysis of a series of substituted phenyl β-acetylglucosaminides ; the substituents are 2, 4-dinitro, p-nitro, 4-nitro-3-methyl, m-nitro, p-chloro, m-chloro, p-methyl, m-methyl, p-methoxy and p-hydroxyl groups. The values were evaluated in terms of the ρ-σ relationship of Hammett. Plots of log Km with respect to Hammett substituent constant, σ and Hansch substituent constant, π showed the enzyme-substrate affinity to be dependent on the electronic nature of the substituents (ρ=-0.42, correlation coefficient γ=0.943) but not on the hydrophobic nature. The log k^rel_cat value was only slightly dependent on σ value (ρ=+0.16, γ=0.626). An experiment on nucleophilic competition with methanol was carried out in an attempt to explain the small ρ value for k^rel_cat. Methanol competes with water for the glycosyl enzyme to some extent but does not increase k^rel_cat for the glycosides examined, indicating that the deglycosylation is not rate-limiting and hence the ρ value for k^rel_cat pertains to the reaction of glycoside bond cleavage.

View full abstract

Six analogues of LH-RH, in which the tryptophan residue in position 3 was replaced by nonprotein amino acids, were synthesized and evaluated for their LH-RH activity. The analogues substituted by amino acids having the fused aromatic ring structure in the side-chain retained relatively high biological activity. In particular, the potency of [3- (1-naphthyl)-L-alanine]³-LH-RH was 187.1% of that of synthetic LH-RH. The results demonstrate that the fused aromatic ring structure of the side-chain in position 3 is a favorable factor, and that the indolyl NH group in the Trp residue is not essential.

View full abstract

The distribution of D-and L-isomers of ¹⁴C-labeled 5-hydroxytryptophan (5-HTP) was comparatively investigated by means of whole-body autoradiography following intravenous and oral administration to rats. The distribution of ¹⁴C-labeled 5-hydroxytryptamine (5-HT, serotonine) and 5-hydroxyindole-3-acetic acid (5-HIAA), the main end product of 5-HTP metabolism, was also studied for comparison purposes. The following differences were found in the distribution pattern of radioactivity between D-and L-isomers of 5-HTP : i) a rapid and appreciable uptake of radioactivity in the brain only by L-5-HTP, but none by D-5-HTP and 5-HT, ii) a high uptake and accumulation of radioactivity in the adrenal medulla by L-5-HTP and 5-HT, but none by D-5-HTP, iii) a high distribution of radioactivity in the skeletal muscle by L-5-HTP, but none by D-5-HTP and 5-HT, iv) a gradual accumulation of radioactivity in the spleen by L-5-HTP and 5-HT, but none by D-5-HTP, v) a high accumulation and retention in the pancreas by both D- and L-5-HTP, but none by 5-HT, and vi) a high absorbability of L-5-HTP from the intestine in contrast to a very limited absorbability of the D-isomer. The distribution pattern, particularly in regard to the brain uptake, of L-5-HTP-¹⁴C did not change substantially upon increasing the oral dosage, in contrast to a significant change observed for L-DOPA. 5-HIAA, when injected intravenously, was found to be eliminated from the body extremely rapidly through the urinary route. These results were discussed with respect to the possible use of L-5-HTP orally as a brain serotonine precursor.

View full abstract

Effects of various constituents of the perfusates on the sulfanilamide absorption were investigated using in situ recirculation perfusion method with the rat small intestine. Constituents employed were salts and chemical which had been used as components in various buffer solutions and these salts were used in a single or in combination with each other. The results revealed that both of the absorption and the transmucosal fluid movement were considerablly influenced by the constituents of the perfusates. Some salts exhibited lethal effects during the course of the experiment. These results were not able to rule out by pH of the perfusates. However, it was found out that these results had one regression line which was the same as that obtained from the perfusates containing different concentrations of sodium chloride. Taking these lines of evidences into accounts, the protocol in the determining the absorption using the in situ recirculation perfusion technique was proposed and discussed.

View full abstract

Two new alkaloids, syneilesine and acetylsyneilesine, together with senecionine have been isolated from the roots and aerial parts of Syneilesis palmate MAXIM. (Compositae). The structures of syneilesine and acetylsyneilesine were shown to be (12R), (13R), (14R)-15-ethyl-12, 14-dihydroxy-4, 12, 13-trimethyl-8-oxo-4, 8-secosenec-1-enine and (12R), (13R), (14R)-14-acetoxy-15-ethyl-12-hydroxy-4, 12, 13-trimethyl-8-oxo-4, 8-secosenec-1-enine, respectively.

View full abstract

In the chloroform solution of tetrahydroprotoberberine-type alkaloids, the position of the equilibrium should be shifted to the B/C-trans side overwhelmingly in the alkaloids of group I (e.g., tetrahydropalmatine), considerably to the B/C-cis side in the group III (e.g., mesocorydaline), and to the B/C-cis side compared to that of group I and to the B/C-trans side compared to that of group III in the alkaloids of group II (e.g., capaurine), in which the amount of the B/C-cis form increases according to the bulkiness of substituent at C-1. In the crystal state, both the racemates and optically active compounds of groups I and III can adopt the preferred conformation present in the solution, while in the group II, the crystal contains one of the conformations and in certain cases, it adopts a different conformation between optically active compound and racemate.

View full abstract

The acid dissociation equilibria in aqueous solution of tyrosine and its related compounds were determined by potentiomeric titration and absorption spectra at 25° and μ=0.1 (NaClO₄). Microscopic equilibrium constants were calculated by three different methods. In method A, the absorbance at 295 nm is a measure of the total concentration of the dissociated phenol. Method B is based on the assumption that k₂ is the same as the dissociation constants of dimethoxy-phenyl or phenyl derivatives. Method C is a modification of the Edsall method. Tyrosine, m-tyrosine, and octopamine were found to be present in maximum amount as the amino-phenol form at pH 9.5, whereas tyramine was found to be present in about 30% as a zwitter-ionic form at pH 10. From the values obtained, pK₂ values seem to contribute to the dissociation of phenol group in tyrosine, m-tyrosine, and octopamine, while the dissociation of phenol group may contribute to the value of pK₁ in tyramine.

View full abstract

Effect of stannous chloride on the urinary calcium concentration was examined in rats intraperitoneally administered with stannous chloride. The concentration of calcium in urine was significantly decreased by the administration of stannous chloride (Sn 3.0 mg/100 g), while the concentration of inorganic phosphorus was not altered markedly. The reduction of calcium concentration in the urine, induced by stannous chloride, was not restored by the injection of calcium in rats treated with stannous chloride. The present study indicates that the administration of stannous chloride inhibited the excretion of calcium into urine of rats.

View full abstract

Investigations were carried out to determine whether or not a decreasing action of hepatic glycogen content in rats by ginseng extract is due to its main constituent, saponin. The experimental results suggested that ginseng saponin decreases the glycogen stores, but the degree of its effect is regulated by the nutritional status of rats.

View full abstract

N-Methyloxazolium salts were converted to the corresponding N-methylimidazoles in ethanol-ammonia. N-Benzyl-4-methyl-5-phenyloxazolium salt (IIe) was also converted to the N-benzylimidazole (IVe) which was debenzylated by the known method.

View full abstract

Some effects of dosage form on absorption of vitamin A into thoracic duct were studied in rats fed vitamin A. Forty-five % of administered vitamin A was recovered in lymph when vitamin A was given in micellar solution form, while 29% of administered vitamin A was recovered when vitamin A was given in triolein solution form. The time courses of appearance of vitamin A in lymph of these two kinds of preparation were very different one another. Vitamin A appearance in lymph showed a sharp peak between 1 and 2 hr after the administration in micellar solution form and indicated the almost complete absorption of vitamin A, while it showed a broad band over 4 hr after the administration in oily solution form. The time courses of vitamin A in serum did not exactly reflect those in lymph.

View full abstract

From the dried mixture of buds and flowers of Panax ginseng C.A. MEYER, there were isolated and identified ginsenosides-Rd (I), -Re (II), and -Rg₁ (III), all of which were already isolated from Ginseng roots. The high yield (ca. 2.5%) of II from the buds and the flowers is significant with respect to the source of this saponin and its aglycone, 20 (S)-protopanaxatriol.

View full abstract

Five species of red algae were examined for sterols. Desmosterol was identified in Porphyra tenera, Ptilota pectinata and Rhodymenie palmate and the last algae was found to contain liagosterol (I) and cholesta-5, 25-dien-3β, 23-diol (II)

View full abstract

17β-(3-Furyl)-5β, 14β-androstane-3β, 14β-diol, a promissing relay compound leading to digitoxigenin, was synthesized starting with 3β-acetoxy-5β-pregn-14-en-20-one.

View full abstract

A new triterpene glycoside (I) named acetyl shengmanol xyloside, mp 280-281°, [α]²⁷_D-23.7°, which was isolated from the underground part of Gimicifga japonica, yielded an amorphous aglycone (XII) on enzymatic hydrolysis. The peracetate of I afforded mainly 25-O-methylcimigenol (IV) along with cimigenol (V) and isodahurinol (VI) on acidic hydrolysis, while I gave cimigol xyloside (III), mp 297-299°, on alkaline treatment. The degradation of I with meta-periodate-cyclohexylamine gave an aldehyde-carboxylic acid, methyl ester of which has structure (IX). From chemical and spectral evidence, the structure of acetyl shengmanol (XII) was proposed to be (23R, 24S)-24, 25-epoxy-3β, 15ξ-dihydroxy-23-acetoxy-9, 19-cyclolanost-16-one. I is so unstable that it is readily convertible to cimigol xyloside (III) on alkaline treatment and to cimigenol (V) during acid hydrolysis. XII seems to be a precursor of cimigenol and cimigol in C. japonica. The mechanism of transformation of XII to V and VII was discussed.

View full abstract