The action of three synthesized peptides allied to bradykinin, i.e., [Ser(Ac)6]-bradykinyl-Gly-Val-Gln (III), Gly-Gly-Lys-[Ser(Ac)6]-bradykinin (IV), and bradykinylglycine (V), for contraction of excised ileum of a guinea pig was compared with that of bradykinin (I). Activities of these peptides after incubation with trypsin (pH 8.0) at 37° for 50 min was examined with ileum contracting action as the indicator in order to examine their properties as the so-called "low-molecular kininogen" -like peptides. IV possessed a comparatively strong activity, being 3.5% of that of I but that of III and V was weak, being 0.03% and 0.14% of I. Trypsin treatment markedly increased the activity, that of III becoming 67% and that of IV to 32% of I. This fact suggests that trypsin treatment has effected not only the liberation of [Ser(Ac)6]-bradykinin (II) but hydrolysis of the ester in the O-acetylserine residue also occurred at the same time to liberate I. The activity of V after its trypsin treatment was 2.3% of that of I. Comparison of this fact with the trypsin treatment of III suggests that when a free carboxyl group is present in the glycine residue of C-terminal arginine-glycine bond in V, it seems difficult for trypsin to sever the peptide chain.
Polarographic reduction of androsten-3-ones, androsten-7-ones, and pregnen-20-ones was carried out in aqueous dimethylformamide solution and the relationship between the half-wave potential and the nature of the conjugated ketone system, i.e., the position of the carbonyl group and the number of the double bond, was examined (Tables I, III, and IV). In each series, the more the conjugated double bond was elongated, the easier was the reduction of unsaturated ketone. The result of controled-potential electrolysis with some unsaturated ketosteroids revealed the electron-number that participated in the polarographic reduction (Table II).
Stability of 1, 2-dimethyl-3-phenyl-4-imidazolidinone (IMO-1) was examined kinetically. It was found that IMO-1 was decomposed to α-methylaminoacetanilide and acetaldehyde in acidic media by the pseudo-first order reaction. In neutral and alkaline media, these products were also formed but the equilibrium between these three compounds was readily established. The pH-profile of decomposition rate constants showed a bell-shape pattern which had a maximum value between pH 5 and 6. The reverse reaction rate was enhanced by the increase of basicity and, therefore, decomposition of IMO-1 decreased. The inflexion point of pH-profile corresponded to the pKa value of IMO-1 (3.8) in acidic region. It was suggested that the reaction rates were influenced by the ionic nature of the compound in solution.
Stability of considerably labile imidazolidinone derivatives substituted at 2-position, such as 1-methyl-2-isopropyl-3-phenyl-4-imidazolidinone (IMO-2) and 1-methyl-2, 3-diphenyl-4-imidazolidinone (IMO-3), was examined kinetically. It was found that IMO-2 had a decomposition pattern similar to that of IMO-1 previously reported. Contrary to IMO-1 and IMO-2, the decomposition of IMO-3 proceeded by the pseudo-first order reaction over the whole pH region. Since benzaldehyde and α-methylaminoacetanilide did not participate in the reversible reaction at pH 7, it was evident that in neutral and alkaline region IMO-3 also decomposed by the pseudo-first order reaction. The pH-profile of the decomposition rate constant of IMO-3 showed a bell-shape pattern having a maximum value in pH 5. The relative decomposition rates of IMO-1, IMO-2, and IMO-3 at pH 5 decreased in the order of IMO-2, IMO-1, and IMO-3.
The stability of 3-phenyl-4-imidazolidinone (IMO-4), a parent derivative in the imidazolidinone series, was kinetically investigated. IMO-4 was found to be markedly more stable than the previously reported derivatives having substituents at 2-position. The behavior of IMO-4 in decomposition was similar to those of the 2-substituted derivatives in the region of pH 3.5-10, the decomposition resulting in the formation of formaldehyde and glycylaniline. In addition, the decomposition proceeded in apparent first order with respect to IMO-4 at pH 3.5-5, and a reversible reaction at pH 6-10, reaching a chemical equilibrium. At pH values below 3 or above 10, however, a different decomposition mechanism was observed. In these regions direct formation of aniline was predominant over the formation of formaldehyde and glycylaniline. Hydrolysis of the latter compound was brought about mainly by the participation of H+ or OH-, and a high acidity or basicity rapidly increased the decomposition rate.
The stability of various imidazolidinone derivatives was examined and it was found that the 2-substituted derivatives were comparatively unstable and that the substituent introduced into the phenyl attaching at the 3-position of the imidazolidinone ring affected the decomposition rate. Such unstability seemed to be due to steric hindrance and electron effect. In rapidly decomposed derivatives, the pH-profile of apparent decomposition rate constants was a bell-shaped curve. It was assumed that the bell shape of the pH-profile over the whole pH region was brought about by the main participation of OH ion in the decomposition of protonated molecules in acidic region and by the predominance of decomposition rate of the intermediate carbinolamines over the rate-determining step with a resultant decrease in the decompo-sition rate in neutral to alkaline region.
The stability of 1, 2-dimethyl-3-phenyl-4-imidazolidinone (IMO-1) with a fast decomposition rate and 3-phenyl-4-imidazolidinone (IMO-4) with a low rate in rat blood was investigated. Both α-methylaminoacetanilide (IMO-D) and glycylaniline, which are decomposition products of IMO-1 and IMO-4, respectively, were metabolized to aniline in blood. It was found that the decomposition rate of glycylaniline was much larger than that of IMO-D. On the other hand, acetaldehyde produced from IMO-1 disappeared rapidly from blood by the attack of enzymes and protein binding. This result strongly suggested that IMO-1 was scarcely affected by the contribution of a reversible reaction, and appeared to be rapidly broken down by the first-order reaction in blood. These facts reveal that IMO-1 easily produced aniline, in contrast to IMO-4 which was quite stable and does not form aniline in blood.
Adsorption of polyvinylpyrrolidone (PVP) from aqueous solution on chloramphenicol was measured. The adsorption data fitted the Langmuir isotherm. The adsorption capacity (χ∞) slightly increased with molecular weight (M) according to the relationship χ∞=KMα, where α was 0.11. Assuming that PVP molecules lie flat on the surface of chloramphenicol particles, χ∞ in all cases corresponds to 2-3 molecular layers. The amount of PVP adsorbed increased with temperature. This apparent decrease in free energy is associated with a large positive entropy contribution due to the liberation of water molecules from the polymer and the aqueous-solid interface. The protective action of PVP on chloramphenicol suspension was also determined by the sedimentation volume (SV) method. The SV decreased with molecular weight of PVP and increased with rising temperature. The stabilizing effect of PVP on the chloramphenicol suspension can be plausibly explained on the basis of the thermodynamic properties of aqueous solution of PVP and the configuration of PVP adsorbed.
Gas chromatographic separation of the derivatives of β-hydroxyalkanoic acids ranging from C6 to C18 was investigated. Separation into each member of the trimethylsiloxy-trimethylsilyl esters, the trimethylsiloxy-methyl esters, or the hydroxy-methyl esters was attempted by using a series of commercially available stationary phases with a hydrogen flame ionization detector system. As methyl esters, α-and β-hydroxyalkanoic and n-alkanoic acids were well separated from each other on a 3% HI-EFF 8B column. Further, a mixture of methyl β-hydroxyalkanoates ranging from C6 to C18 was successfully separated by a programmed temperature gas chromatography.
Controled catalytic hydrogenation of arglanine (I) in the presence of Adams catalyst gave vulgarin (II) and 11-epivulgarin (III). The hydrogenation of douglanine (VII) under the same conditions exclusively yielded the dihydroderivative (VIII) with its 11-methyl group in α (quasiequatorial) configuration. Configuration of the hydroxyl group at C-1 of douglanine is discussed on the basis of chemical evidences.
Reaction of 3-(2-furyl)-3-oxo-1-propenyl-1-trimethylammonium chloride (3) with sodium benzoate, nitrobenzoate, furoate, and 5-nitro-2-furylacrylate afforded the corresponding oxopropenyl esters. cis, cis-2, 4, 6-Trifuroylmethylene-1, 3, 5-trithiane (12), obtained by the application of sodium hydrosulfide to 1-chloro-3-(2-furyl)-1-propen-3-one (1), was found to exist as thiol thioaldehyde tautomers in the presence of alkali. Application of hydrazine, hydroxylamine, diazomethane, and phenylazide to 1-chloro-3-(5-nitro-2-furyl)-1-propen-3-one (2) afforded the respective pyrazole, isoxazole, acylpyrazole, and acyltriazole.
Ring opening of N-(2, 4-dinitrophenyl)pyridinium chloride (1) with acylhydrazine or arylhydrazine derivatives followed by cyclization of the resulting 5-(2, 4-dinitroanilino)-2, 4-pentadienal hydrazone (2a-l) gave N-acylimino or N-aryliminopyridinium betaines (3a-l) (Table I). N-Substituted imino-3-picolinium (3m-o), N-substituted imino-3, 5-lutidinium (3p-r), and N-substituted iminoisoquinolinium betaines (9a-l) were also prepared from 3-picoline, 3, 5-lutidine, and isoquinoline, respectively, by a similar procedure (Table II and III).
The oxidative degradation of isoniazid (INAH) with Cu2+ was investigated. The reaction products were isonicotinic acid, isonicotinamide, 1, 2-diisonicotinoylhydrazine, and isonicotinaldehydeisonicotinoylhydrazone. In the low pH region, the sum of the molar concentration of INAH and degradation products in the solution was equal to the initial molar concentration of INAH in a given kinetic run. It was found that INAH forms chelates with Cu2+ in the 1 : 1 and 1 : 2 ratio and these chelates are degraded by a first-order process, and that the apparent degradation velocity is determined by the concentration of each chelate compound, INAH-Cu+ and INAH-Cu-INAH, and each degradation rate constant. The activation energy of the degradation reaction of INAH-Cu+ and INAH-Cu-INAH was 16.3 and 12.3 kcal/mole, respectively. The degradation of INAH with Cu2+ is accomplished by two steps ; first, Cu2+ chelates with INAH and pulls the electron and then cleaves C=N or N-N bonds. The effect as stabilizer was investigated with few compounds which can be used as pharmaceutics. It was found that EDTA is the most effective and that citric acid has some effect.
Oxidative degradation of isoniazid (INAH) with Mn2+ was examined and the result from the analysis of reaction products shows that the main products are isonicotinic acid and isonicotinamide, and a small amount of by-products are 1, 2-diisonicotinoylhydrazine and isonicotinaldehydeisonicotinoylhydrazone. It was found that INAH makes chelates with Mn2+ in the ratio of 1 : 1 and 1 : 2, these chelates are oxidized to Mn3+ compounds by oxygen and then degraded, and that apparent degradation velocity of INAH is determined by the concentration and degradation rate of each of the chelates. The activation energy of the degradation reaction of chelate compounds, INAH-Mn+ and INAH-Mn-INAH, was 11.7 and 10.0 kcal/mole, respectively. The degradation of INAH with Mu2+ is accomplished by a three-step process ; first Mn2+ forms a chelate with INAH, then Mn2+ of the chelate is oxidized to Mn3+ by oxygen, and then the high electron affinity of Mn3+ cleaves the C=N and N-N bonds.
The degradation of isonicotinic acid hydrazide sodium methanesulfonate (IHMS) was examined in aqueous solution (pH 3.0-9.0). Isoniazid (INAH) and little unknown compound were found as degradation products and in addition to them, isonicotinic acid and 1, 2-diisonicotinoylhydrazine were found at pH 9.0. For the assay method, only IHMS was eluted from the sample solution by ion exchange resin, Amberlite CG-50 (H+), and the effluent submitted to colorimetry. This method gave satisfactory results. With this method, degradation of IHMS was examined and it was found that the main degradation in the reaction of IHMS is a catalytic reaction of OH- to IHMS anion, that equilibrium of IHMS concentration is established relatively rapidly, and that INAH and sodium hydroxymethanesulfonate (OMS) produce IHMS. The stabilizing effect of INAH and OMS, which are degradation products of IHMS, and NaHSO3, and formaldehyde, which are the degradation products of OMS, was investigated when they are added previously to the reaction system. OMS was found to be more effective.
Chemical constituents of Corydalis pallida PERS. var. tenuis YATABE were studied. A new natural alkaloid, d-tetrahydrocorysamine was isolated from the whole herb of this plant, together with dihydrosanguinarine, oxysanguinarine, protopine, l-tetrahydropalmatine, d-corydaline, capaurimine, capaurine, capauridine, l-scoulerine, the so-called l-corydalmine, ginnol, and trans-3-ethylidene-2-pyrrolidone. From the quaternary base fraction, sanguinarine, corysamine, coptisine, and dehydrocorydaline were detected by means of a thin-layer chromatography. At the same time, the structure of capaurimine was revised to 1, 10-dihydroxy-2, 3, 9-trimethoxydibenzo[α, g]quinolizidine (V) on the basis of nucler magnetic resonance and mass spectra.
Absorption, distribution, and excretion of 3H-pregnanediol after its percutaneous or intraperitoneal administration in female mice and rats were studied by autoradiography and liquid scintillation counting. Examination of absorption showed that 14% of the percutaneously administered radioactivity was absorbed during 48 hours. Microautoradiograms of rat skin applied with 3H-pregnanediol ointment suggested that the drug was absorbed through stratum malpighi of the cuticle and hair-follicles. Thirty minutes after intraperitoneal injection of 3H-pregnanediol in female mice, high concentration of the radioactivity was found in the gall bladder and intestinal content. A moderate level of the radioactivity was observed in the liver. Levels of radioactivity in other tissues were as low as that in blood. The lowest concentration was found in the brain. Twenty-four hours after intraperitoneal administration radioactivity in various organs except in intestinal contents decreased markedly.
As an approach to detection and characterization of a minute amount of O-glycosides, high resolution mass spectra of 24 kinds of simple alkyl and aryl hexopyranosides and furanosides were taken in the form of their peracetates, and the most probable fragmentation processes of the sugar moieties and the differences in their cracking patterns due to variation of the aglycone and ring size of the sugar part are presented. All alkyl and aryl hexosides so far examined gave, more or less, the ions of c- and e-series fragmentations, which were reported by Biemann to be characteristic of hexopyranose pentaacetates. Alkyl pyranosides and furanosides yielded the fragment ions of d-, e- and g-series accompanied by those of c-series with much smaller intensities. By contrast, in aryl hexosides the ions of c-series were most intense, those of e-series were weak, and none of d- and g-series was observed. Cyclohexyl glucopyranoside showed the ions of e-series most distinctively. Alkyl pyranosides gave the d-series ions most intensively and were differentiated from alkyl furanosides in which the i-series ions were predominant. Aryl pyranosides were not sharply distinguished from the corresponding furanosides.
Inhibitory effect of aminoethylisothiuronium (AET) and its derivatives on dopamine-β-hydroxylase was examined. Among the tested compounds, 2-aminoethyl-N-α-naphthyl-isothiuronium bromide hydrobromide (AENT) was the most active inhibitor. Inhibition by AENT was not competitive with substrate and was not affected by cosubstrate, i.e., bycorbic acid or fumaric acid, but was reversed as addition of Cu2+. Structure-activity-relationship between the AET derivatives and the inhibitory effect on dopamine-β-hydroxylase was discussed.
The essential oil of Kam-seh-chang, a kind of Acorus gramineus SOLAND. in Taiwan was reexamined by gas-liquid chromatography. The oil, obtained in 0.5% yield from fresh leaves, was mainly consisted of methylchavicol amounting to 93.6%, together with traces of α-pinene, camphene, and β-pinene ; limonene 0.2%, 1, 8-cineole 0.1%, p-cymene 0.4%, linalool ( ? ) 0.3%, traces of α-ylangene and β-elemene ; α-selinene 2.0%, anethole 0.3%, methyl-eugenol 0.5%, p-anisaldehyde 0.6%, cis-methylisoeugenol 0.3%, trans-methylisoeugenol trace, β-asarone 0.2%, p-methoxycinnamicaldehyde 1.0%, and other compounds. From the view-point of chemical systematics, this plant will be a new variety of Acorus gramineus SOLAND. and may be considered to be the ancestor of the ordinary one, containing cis- and trans-asarone as the main constituents.
Treatment of heteroaromatics of pyridine series with hydrogen peroxide-sodium tungstate in the presence of EDTA at 60-65° gave the corresponding amine oxides in generally good yields. The reactions in the absence of EDTA gave somewhat inferior results. 2-Aminoquinoline was oxidized to 2-aminoquinoline 1-oxide and 2-nitroquinoline. This procedure is rather simple and worth trying for preparation of aromatic amine oxides in some cases.
The methanol extract of the leaves of Tripetaleia paniculata was examined and a substance was detected which has chemical characters like grayanotoxin-I, -II, and III-, and lyoniol-A, but did not agree with any of them. Compounds other than the toxic principle isolated and identified were normal higher aliphatic hydrocarbons, higher primary alcohols, higher ketones, ursolic acid, and monotropein. Maslinic acid and 2α-hydroxyursolic acid were obtained as a mixture which was converted into diacetate methyl ester, analyzed by gas-liquid chromatography, and the amount of each component was found to be roughly equal.