The metabolic fate of ¹³¹I-urokinase in rats and dogs was investigated. The radioactivity in the blood of both animals after intravenous administration rapidly decreased in early stage, followed by a slow decrease of the radioactivity. When ¹³¹I-urokinase was given into rats by intravenous infusion, the peak of radioactivity in the blood was found at the end of the dosing period. The radioactivity in the liver and kidneys of the rats 15 min after intravenous administration of ¹³¹I-urokinase was found to be 43 and 32% of the administered radioactivity, respectively. In the rats approximately 80% of the administered radioactivity was recovered, mainly in the urine in 3 days. The radioactivity derived from high-molecular compounds in the serum of rats receiving ¹³¹I-urokinase intravenously was approximately 95% of the radioactivity detected 1 min after dosing, 70% at 20 min and 40% at 60 min. An artificial thrombus was prepared by the method of Chandler and radioactivity of the thrombus was determined by incubating with radioiodinated urokinase, plasminogen, plasmin or reference compounds. After a 6 hr incubation the ratio of the radioactivity concentration of the thrombus (cpm/mg) to that of the blood (cpm/mg) was 2 for ¹³¹I-urokinase, 3 for ¹³¹I-plasminogen, 3 for ¹³¹I-plasmin, 0.7 for ¹³¹I-human serum albumin and 0.8 for Na¹³¹I. When the blood added with ¹³¹I-plasminogen was employed for the preparation of an artificial thrombus, approximately 15% of the added radioactivity was detected in the thrombus.

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Irradiation of o-alkylbenzaldehyde, i.e., o-methylbenzaldehyde and o-benzylbenzaldehyde gave the corresponding enoles, which gave dimethyl naphthalene-2, 3-dicarboxylates, 4-hydroxy-1-phenyl-1, 2, 3, 4-tetrahydronaphthalene-2, 3-dicarboxylic acid γ-lactones and phthalides by reaction with dimethyl acetylenedicarboxylate, maleic anhydride and oxygen, respectively.

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N-Benzenesulfonyl Reissert compound was converted to isoquinaldonitrile with sodium borohydride under very mild reaction conditions and also the N-benzoyl Reissert compound underwent the reductive fission with sodium borohydride. The latter was applied to the synthesis of 1-alkylisoquinolines.

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Reaction of ethyl α-(dimethylaminomethylene)-2-pyridineacetate (I) with acetic anhydride gives ethyl 4-oxo-4H-quinolizine-1-carboxylate (Va). Similar reaction with acid anhydrides, such as propionic anhydride and n-butyric anhydride, affords the corresponding 3-substituted-quinolizine derivatives (Vc and Ve). Similarly, α-(dimethylaminomethylene)-2-pyridineacetonitrile (II) and quinolyl homologous (III and IV) react with acid anhydrides to give the corresponding 3-substituted-4-oxo-4H-quinolizine-1-carbonitrile (Vb, Vd and Vf), ethyl 2-substituted-1-oxo-1H-benzo [c] quinolizine-4-carboxylate (VIa, VIc and VIe) and 4-carbonitrile derivatives (VIb, VId, and VIf), respectively. I reacts with diethyl malonate to give diethyl 4-oxo-4H-quinolizine-1, 3-dicarboxylate (Vg). Similar reaction with esters, such as ethyl cyanoacetate, ethyl acetoacetate and ethyl 2-pyridineacetate, affords the corresponding 3-substituted-quinolizine derivatives (Vi, Vk, and Vm). II, III and IV react with esters to form quinolizine and benzoquinolizine derivatives (Vh, Vj, Vn, VIg, VIh, VIi, VIj, VIk, and VIl). Reaction of III with esters affords ethyl 2-(2'-quinolyl)-1-oxo-1H-benzo [c] quinolizine-4-carboxylate (VII), besides the expected product (VIg, VIi, VIk). Reaction of IV with ethyl acetoacetate gives ethyl 3-(2'-quinolyl)-6-methyl-2-pyridone-5-carboxylate (IX) as a main product (33%).

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The effects of preincubation of microsomes with ascorbate or ferrous ion or NADPH-generating system on activities of drug metabolizing enzymes, content of cytochrome P-450 and the activities of NADPH-linked cytochrome c reductase and neotetrazolium diaphorase were investigated. Demethylase activities of aminopyrine, ethylmorphine and codeine were markedly decreased by the stimulation of microsomal lipid peroxidation whereas hydroxylation of aniline was only slightly reduced. On the other hand, content of cytochrome P-450 and activities of NADPH-cytochrome c reductase and NADPH-neotetrazolium diaphorase were only slightly changed by the stimulation of microsomal lipid peroxidation. Aminopyrine N-demethylation was inhibited by carbon monoxide but lipid peroxidation was increased. Furthermore, synergism of NADPH-dependent drug oxidation by NADH which has been reported by Estabrook, et al. was not observed in lipid peroxidation.

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Attempted synthesis of 3-substituted (alkoxycarbonyl, hydroxymethyl or cyano)-2, 3-dihydro-2-benzyl (acyl or alkoxycarbonyl)-1H-pyrrolo [3, 4-b] quinolines (II), (III), and (VI) as potential ring A-B-C components for a total synthesis of dl-camptothecin (I) is described.

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A D-E ring analog (XX) of camptothecin (I) was synthesized from 4-methoxy-1-methyl-2 (1H)-pyridone by using Vilsmeier reaction followed by nucleophilic direct introduction of di-tert-butyl malonate onto the pyridone ring, ethylation and hydroxylation.

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dl-Camptothecin (XXX) and two epimeric N-formyl-1, 2, 6, 7-tetrahydrocamptothecins (XXIIIa, b) have been synthesized from 3-oxo-1H-pyrrolo [3, 4-b] quinoline IIIa by using following two key reactions. 1) An intramolecular aldol condensation of the imido-ester (VIIIb→IXb). 2) Vilsmeier reaction on a 4-methoxy-2-pyridone ring (XVIb→XVII) followed by nucleophilic attack of a malonate carbanion onto the formyl-pyridone ring (XVII→XVIII).

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(±)-Hasubanonine was synthesized through 16-oxo-hasubanonine (63) as a relay substance starting from the keto-lactam (41). The keto-lactam (41) was derived to the keto-O-acetyl-phenol A (49) which was oxidized to the axial-acetoxy-ketone (50). Bromination of (50) followed by the rearrangement reaction with sodium acetate gave the enol-acetate (51) which was converted to the bromo-enolmethyl-ether (56) via the diosphenol (54) and the bromo-diketone (55). The compound (56) was derived to the β-diketone (57) which was methylated to give (±)-16-oxo-hasubanonine (59) and (±)-aknadilactam (61). On the other hand, hasubanonine was oxidized to 16-oxo-hasubanonine (63) which was put back to hasubanonine by lithium aluminum hydride reduction followed by manganese dioxide oxidation.

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On ultraviolet irradiation in the presence of sodium borohydride, 4-thiouracil (1a), 4-thiouridine (1b) and 2-thiouracil (3a) were readily reduced to 2-oxohexahydropyrimidine (2a), its riboside (2b) and 1-(3-hydroxypropyl) thiourea (4), respectively. By controling the energies of the ultraviolet light in the region below 300 nm the selective photoreduction of these thiopyrimidines was demonstrated, while uracil and uridine were unaffected under these conditions. Photochemical behavior of the thiopyrimidines was discussed.

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Formosan ferns from 17 families, representing 50 genera, 115 species, 1 subspecies, and 3 varieties, have been screened by the bioassay for phytoecdysones. A total of 64 species and 2 varieties have been found to show distinct insect moulting hormone activity. Correlation between this hormone activity and taxonomy of ferns is discussed.

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Proton magnetic resonance spectra of some methylpiperidinium salts were taken in various solvents and at various concentrations. Chemical shifts of the N-methyl protons were strongly dependent on solvent and concentration. Those at the infinite dilution were dependent on solvent but not on the counter anion, indicating that the free cation exists as a solvated form. Those of the ion-paired forms were also dependent on solvent. The effects of the solvent and counter ion on the chemical shift are discussed.

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Effect of potassium ion on the intramuscular absorption of some drugs has been examined using the rat thigh muscle clearance method. In the presence of K⁺ (<200 mM), a specific and reversible inhibition was noted in the absorption of anionic drugs such as isonicotinic acid, PABA, and sulfa drugs. This inhibition of anionic drug absorption produced by K⁺ was reversed by DNP and KCN, but was not abolished by ouabain. This inhibition was minimized by the addition of EDTA. Extracellular K⁺ of high concentration produced by anionic drugs may cause the increase of Ca⁺⁺ entry into the muscle tissue, which inhibits the drug transfer in the muscle by some unknown pharmacological actions.

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Besides sennoside A, sennosides B, C, E and F were isolated from rhubarbs. Sennosides E and F are new compounds and have comparable purgative activity to other sennosides. Sennosides E and F are stereoisomer mutually, and they are oxalates of sennosides A and B, respectively. Although sennoside A was able to be isomerized to sennoside B irreversibly, the plant contained more of the former.

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The adducts of phosphorus compounds and tetrahalomethanes were applied to peptide synthesis as condensation reagents. Several kinds of phosphorus compounds, tetrahalomethanes, bases, and solvents were investigated for the Young racemization test and the racemization-free reaction conditions were established.

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Some di and tripeptide derivatives containing various kinds of α-amino acids were synthesized with our new method using the adducts of phosphorus compounds and tetrahalomethanes to investigate the effects of the reaction on the side chains of amino acids. Mechanisms of this novel reaction were also discussed.

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Preliminary investigations on the interaction between diethyl phosphorazidate and benzoic acid revealed that phosphoryl azides may be a convenient reagent for a modified Curtius reaction and the amide bond formation. Among phosphoryl azides, diphenyl phosphorazidate (DPPA) which was easily prepared by the action of sodium azide on diphenyl phosphorochloridate was chosen for the investigation on the racemization-free peptide synthesis. The Young test under various conditions proved that DPPA may be a new convenient reagent for the racemization-free peptide synthesis. The results are summarized in Tables.

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The peptide bond formation reaction by some analogs of diphenyl phosphorazidate (DPPA) was investigated, proving that DPPA is much superior in the Young test to diethyl phosphorazidate, di-p-nitrophenyl phosphorazidate, dimorpholyl phosphorazidate, and diphenyl phosphorochloridate. Some spectroscopic investigations on the DPPA method were also made. Possible mechanisms for the DPPA method are presented in Chart 1.

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Application of diphenyl phosphorazidate (DPPA) to the synthesis of peptides revealed that the DPPA method is quite general because it can be applied to the formation of peptides containing various functional groups. No difficulties were encountered when the side chains of serine, threonine, valine, glutamine, asparagine, methionine, histidine, tryptophan, and pyroglutamic acid were present in the carboxyl component. Arginine and cysteine showed no trouble when their side chain functions were protected with the nitro and benzyl groups, respectively. Serine, tyrosine, and histidine could be used as the amino component without any protection of the side chains. Fragment coupling of N-benzyloxycarbonylleucylleucine with valylphenylalanine methyl ester hydrochloride by DPPA showed that no racemization occurred.

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Dimethyl sulfoxide (DMSO) effect on the alkaline hydrolysis rate of amide was studied. Among seven amides studied, i.e., benzamide, p-nitrobenzamide, N-methyl-p-nitrobenzamide, acetanilide, N-methylacetanilide, N, N-dimethylbenzamide and N, N-dimethyl-p-nitrobenzamide, DMSO increased the rates of the last two N, N-dimethylamides, and decreased the rates of the other five amides. Since DMSO increased the ester alkaline hydrolysis rates with desolvation of hydroxide ion, the rate determining step in N, N-dimethylbenzamides hydrolysis was assumed to be the OH^- addition to carbonyl carbon as in ester. And in the other five amides, the rate determining step was assumed to be the leaving of amino group from the tetrahedral intermediate. This assumption was supported by pH dependence of DMSO effect on 2, 2, 2-trifluoro-N-methylacetanilide hydrolysis of which rate determining step depends on hydroxide ion concentration. From this standpoint, as DMSO decreased the hydrolysis rates of hexobarbital and thiamylal, the rate determining step of barbitals was considered to be C-N bond fission.

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The frequencies of the asymmetric stretching vibrations of NO₂ groups of para-and met■-substituted nitrobenzenes and of the stretching vibrations of C≡N groups of aliphatic and aromatic cyano compounds were satisfactorily correlated with their respective π bond orders calculated by the HMO method employing the MASP technique. The usefulness of the application of this technique to the HMO calculation of such aromatic systems as benzophenone derivatives is also described.

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Eight species of Aphyllophorales and one species of Agaricales of Basidiomycetes were examined for the triterpenoidal constituents and six compounds (I, II, III, IVa, VIIIa, IXa) were isolated and identified (Table I). The new acid from Melanoporia rosea (as the methyl ester) (IVa) was suggested to be 12β-hydroxycarbomethoxyacetylquercinic acid methyl ester.

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The action on muscle spindle afferents, sialogogous action and acute toxicity of lyoniol-A and eleven related compounds were determined. The excitatory action on muscle spindle afferents were measured as the increase in frequencies of the afferent discharge from de-efferented muscle spindles in anesthetized rats. LD₅₀-and salivationtests were conducted using mice. Of the compounds studied, lyoniol-A, lyoniol-B, dihydrolyoniol-B, grayanotoxin-I and grayanotoxin-III were more potent than suxamethonium, an established muscle spindle excitant, in causing an increase in afferent discharges from muscle spindles. The action on muscle spindle afferents and acute toxicity of the compounds studied were roughly parallel. The relationship between structure and activity was discussed.

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16-Oxoestradiol (IV), two pairs of isomeric 2-and 3-methyl ethers of 2-hydroxyestriol (II, III) and 2-hydroxy-16-oxoestradiol (V, VI) have been characterized as biliary glucuronide metabolites of estriol in the rat. This is the first report on in vivo formation of catechol estrogen having the 16-oxo-17β-ol structure.

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Aminopyrine and its metabolites, 4-aminoantipyrine and N-acetyl-4-aminoantipyrine, were orally administered to human subjects and cumulative amounts of 4-aminoantipyrine and N-acetyl-4-aminoantipyrine excreted in urine were determined. Pharmacokinetic parameters of aminopyrine were estimated by means of least square fit of multi-exponential equations to the urine data.

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(±)-Metaphanine (49), which is a member of hasubanan alkaloids and possesses an intramolecular hemiketal ring, was synthesized. The keto-lactam (5)³⁾ was derived to the diacetoxy-ketal (13) via the O-acetyl-ketolactam (11). The compound (13) was oxidized to the 10-oxo compound (16) which was reduced stereoselectively to the trans diol-lactam (22), a C₁₀-hydroxy group of which was selectively protected by an acetyl group or by a tetrahydropyranyl group to give the trans 10-acetoxy compound (23) or the monotetrahydropyranyl ether (33), both of which were oxidized and hydrolyzed to provide (±)-7-ethyleneketal-16-oxo-metaphanine (36). The selective reduction of the lactam carbonyl group of the compound (36) by the Borch's method⁴⁾ gave (±)-7-ethyleneketal-metaphanine (44) which was hydrolyzed to give (±)-metaphanine (49).

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Bromphenol blue (BPB) and p-acetylaminohippuric acid (PAAH) were studied with rats to understand the basic principles of hepato-biliary transport process. At higher doses of BPB, the hepato-biliary transport capacity appeared to be saturated. At 30 min after the intravenous administration of BPB (5 μmole/300 g body weight), bile/plasma concentration ratio (B/P ratio) was 894±99, liver/plasma concentration ratio (L/P ratio) was 22±5 and bile/liver concentration ratio (B/L ratio) was 42±8. In the case of PAAH (6 μmole/300 g), B/P ratio was 43±15, L/P ratio was 0.47±0.27 and B/L ratio was 12±30. Sulfobromophthalein (BSP) inhibited the L/P and B/L ratios of BPB and BPB inhibited the L/P and B/L ratios of PAAH. With rat liver cell suspensions, BPB was entrapped very rapidly and its cell/medium concentration ratio was about 21 at 30 μg/ml, which was depressed by BSP. With equilibrium dialysis, 95.6±1.5% of BPB and 11.3±3.4% of PAAH were bound to the liver homogenate. These results suggest that these organic anions are transported from blood into bile at least two processes, namely hepatic uptake and biliary excretion, and that the hepatic uptake of these compounds is mainly due to the binding to the substances which exist in the liver cells.

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Three sulfur-bridged cyclonucleosides, (S)-2, 2'-, 2, 3'-and 2, 5'-cyclo-2-thiouridines (VII, XV, and XIV) have been synthesized. The present synthetic method involves the use of uridine as the starting material through 2-thiouridines as the intermediates. The ultraviolet, optical rotatory dispersion (ORD), circular dichroism (CD), and nuclear magnetic resonance data of these (S)-cyclo-2-thiouridines are presented. (S)-2, 5'-Cyclonucleoside (XIV) was thought to be present as an "endo" conformation in terms of bridging sulfur. The limitation of the applicability of Ulbricht's rule on the correlation of the sign of ORD (CD) and torsion angle around the glycosidic bond was discussed.

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For the purpose of finding out a strain which has stronger cytolytic activity on Ehrlich ascites carcinoma cells, the authors isolated 113 strains of Bacillus natto from straws, which were collected at various areas in Japan, and measured the cytolytic activities by cylinder plate method. As the results, the authors found out a strain of Bacillus natto (tentatively called KMD 2311) which has the strongest cytolytic activity in the 113 strains. There were at least two kind of cytolytic substances on Ehrlich ascites carcinoma cells in the culture medium of Bacillus natto KMD 2311. One was extracted with AcOEt from the culture medium, which constitute approximately 20% of the cytolytic activity in the culture medium and it was stable. This cytolytic substance was purified and colorless crystalline compound (mp 247-249°) was obtained by recrystallization from acetone-petr. ether. Chemical structure of this compound was examined by elementary analysis, infrared, nuclear magnetic resonance, and mass spectroscopy and study of decomposed products. As the results, this compound was proved to be identical with surfactin (mp 140°), which was obtained from culture medium of Bacillus subtilis by Kakinuma, et al. and from Bacillus natto KMD 1126 by the authors. Melting point of this compound (mp 249°) was higher about 100° than that of surfactin (mp 140°), but high mp compound was obtained from surfactin by recrystallization from acetone-petr. ether. From these results, it was indicated that the cytolytic substance was identified with surfactin and dimorphic.

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A diatom, Synedra rumpens KUTZ., was isolated from the water in Lake Biwa which is the source of the water supplies of Kyoto City. Two odorous metabolites produced by this alga were proved to be n-hexanal and n-heptanal by means of gas chromatography (GC) and GC-mass spectrum. Three of four fatty acids obtained from Synedra rumpens KUTZ. were also identified as isovaleric, myristic, and palmitic acids by GC.

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