著者

KAZUO IGARASHI FUMIYO KASUYA MIYOSHI FUKUI

出版者

The Pharmaceutical Society of Japan

雑誌

Journal of Pharmacobio-Dynamics (ISSN:0386846X)

巻号頁・発行日

vol.6, no.8, pp.538-550, 1983 (Released:2008-02-19)

参考文献数

16

被引用文献数

3 4

---

The metabolism of dibucaine was studied in the rat, rabbit and man. A total of ten basic metabolites other than dibucaine were detected in the urine samples of three species by thin-layer chromatography (TLC) and gas chromatography (GC), and structures of these metabolites were identified by comparison of the properties given by TLC, GC and gas chromatography-mass spectrometry (GC-MS) with those of authentic compounds. Four of these metabolites were new metabolites which were found in the rabbit or human urine ; two were identified as the 2', 3'-dihydroxybutoxy product (M-6, diol) and its N-deethyl product (M-2), and others were identified as the 2'-hydroxyethoxy product (M-8, alcohol) and its N-deethyl product (M-3). One of the two hydroxyl groups on M-5 was at 6-position on the quinoline ring, while another was assumed to be at 3'-position on the O-alkyl side chain. There were apparent species differences with regard to the major metabolites found in each species ; i.e. M-10 and M-5 in rat, M-6 and M-4 in rabbit, and M-8 and M-4 in man. Small amounts of the conjugated basic metabolites were observed in the urine of all three species. The new metabolic pathways to the diols (M-2 and M-6) or the alcohols (M-3 and M-8) were also discussed.

著者

KAZUO IGARASHI FUMIYO KASUYA MIYOSHI FUKUI HISASHI NANJYOU

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.7, pp.3033-3036, 1987-07-25 (Released:2009-10-19)

参考文献数

9

被引用文献数

4 5

---

A high-performance liquid chromatographic (HPLC) method using a fluorescence detector is described for the simultaneous determination of dibucaine and its metabolites (M-4, M-8 and M-10) in human urine. Urine samples from obstetric patients were chromatographed in a reversed-phase system. When a ultraviolet detector (320 nm) was used, some interfering peaks appeared on the chromatogram, but this interference could be overcome by employing a fluorescence detector (Ex 330 nm and Em 440 nm) instead. The calibration curves were linear in the range of 0.05-5.0 μg/ml for all compounds and the detection limits of dibucaine and its metabolites were about 5 ng/ml in urine. The urinary excretion of dibucaine and its metabolites by obstetric patients infused with Percamine S® in the spinal cord were determined. The mean cumulative amounts of dibucaine, M-4, M-8 and M-10 excreted during 10 h after administration were 1.1, 10.5, 3.5 and 1.1 % of the dose, respectively. The total urinary excretion was 16.2% of the dose. This method is sufficiently sensitive and specific to permit the determination of dibucaine and its metabolites in biological fluids.

著者

落合 英二 金子 主税

出版者

The Pharmaceutical Society of Japan

雑誌

Pharmaceutical Bulletin (ISSN:03699471)

巻号頁・発行日

vol.5, no.1, pp.56-62, 1957-02-20 (Released:2008-02-19)

被引用文献数

2 10

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Durch Nitrierung von Chinolin-N-oxyd mit Benzoylnitrat in Chloroform-bzw. Dioxan-Losung wurde das 3-Nitrochinolin-N-oxyd mit befriedigender Ausbeute erhalten. Pyridin-N-oxyd gibt bei ganz analoger Reaktion das 3-Nitropyridin-N-oxyd trotz sehr schlechter Ausbeute. UV-Absorptionsspektren der isomeren Mononitroderivate des Chinolin-N-oxydes wurden verglichen.

著者

落合 英二 池原 森男

出版者

The Pharmaceutical Society of Japan

雑誌

Pharmaceutical Bulletin (ISSN:03699471)

巻号頁・発行日

vol.3, no.6, pp.454-458, 1955-12-20 (Released:2008-02-19)

被引用文献数

11 17

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Isochinolin-N-oxyd (I) geht beim Erhitzen mit Essigsaureanhydrid in Isocarbostyril (II) uber. Die Reaktion von (I) mit Tosylchlorid begleitet eine andere Umlagerung. (I) gibt beim Erhitzen mit Tosylchlorid in Chloroform eine syrupose Masse, die sich beim Behandeln mit wenig Methanol kristallinisch erstarrt. Sie bildet beim Umkristallisieren aus Methanol Nadeln vom Schmp. 184∼185° (III), deren Analysenzahlen mit C16H13O3NS·C7H7O2ClS ubereinstimmen. Aus ihrer Mutterlauge wurde (II) isoliert. (III) entsteht dabei in uberwiegender Menge. (III) wandelt sich beim Behandeln mit verd. Soda-Losung in Wurfeln vom Schmp. 92∼93° um, von der Zusammensetzung C16H13O3NS (IV), welche als 4-Tosyloxyisochinolin identifiziert wurden. (III) entsteht in praktisch quautitativer Ausbeute, wenn man (IV) mit Tosylchlorid in chloroform erhitzt. Fur die Entstehung von (IV) bzw. (II) aus (I) schlagen die Verfasser eine anionotrope Umlagerung vor. (IV) gibt beim Erhitzen mit Schwefelsaure (38%) oder mit Natronlauge (20%) 4-Oxyisochinolin (V) neben einer kleinen Menge von (II). (V) gibt bei der katalytischen Reduktion mit Platinoxyd in Eisessiglosung 4-Oxy-Bz-tetrahydroisochinolin mit ca. 75% iger Ausbeute.

著者

永吉 剛 佐伯 清太郎 浜名 政和

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.29, no.7, pp.1827-1831, 1981-07-25 (Released:2008-03-31)

参考文献数

27

被引用文献数

4 5

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Treatment of 1-hydroxy-2-phenylindole (1) with phosphoryl chloride-DMF gave 2-phenylindole-3-carboxaldehyde (2) in 70% yield. The reaction of 1 with quinoline 1-oxide (3) and benzoyl chloride in boiling chloroform produced 1-benzoyloxy-2-phenyl-3-(2-quinolyl) indole (5) and 1-hydroxy-2-phenyl-3-(2-quinolyl) indole (6). In the reaction using tosyl chloride instead of benzoyl chloride, 6 or 2-phenyl-3-(2-quinolyl) indole (8) was formed. These results demonstrate that the enehydroxylamine systems in 1 and 1-benzoyloxy-2-phenylindole (4) can behave as nucleophilic species as a result of enamine-like polarization.

著者

吉村 英敏 山本 弘明 佐伯 清太郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.21, no.10, pp.2231-2236, 1973-10-25 (Released:2008-03-31)

被引用文献数

22 23

---

In order to understand the toxic nature of Kanechlor-400 (KC-400, a commercial preparation of polychlorinated biphenyls) and establish the treatment of the patients of this KC-400 intoxication (so-called Yusho), metabolic fate of 2, 4, 3', 4'-tetrachlorobiphenyl (2, 4, 3', 4'-TCB), a major component of KC-400, was investigated using rats. It was found that at least four metabolites having phenolic nature were excreted exclusively into the feces together with a large amount of unchanged 2, 4, 3', 4'-TCB. Among these, a major metabolite (M-A2), mp 155-156°, and a minor metabolite (M-A1), mp 92-98°, were isolated from the feces and characterized to be monohydroxylated TCB by ultraviolet, infrared, nuclear magnetic resonance, and mass spectral analyses. After 2, 4, 3', 4'-TCB was orally administered at a single dose of 25 mg/body to the rat, a little less than one half of the dose was excreted as unchanged 2, 4, 3', 4'-TCB during 12 days, most of which were eliminated in the first day. The excretion of major metabolite reached maximum at the second day, and total M-A2 was accounted for about 10% of dose during 12 days. Both 2, 4, 3', 4'-TCB and its major metabolite were still excreted in a small but significant amount on 12th day.

著者

吉村 英敏 小沢 直記 佐伯 清太郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.26, no.4, pp.1215-1221, 1978-04-25 (Released:2008-03-31)

被引用文献数

53 65

---

The inductive effect of Kanechlor 400 (KC-400), the Japanese polychlorinated biphenyl (PCB) preparation containing 48% chlorine, and several individual PCB isomers on the hepatic microsomal enzymes of rats was investigated. Pretreatment with KC-400 increased significantly the activity of microsomal aminopyrine (AM) demethylase, aniline (AN) hydroxylase and NADPH-cytochrome c reductase, and the content of cytochromes P-450 and b5 just like phenobarbital (PB)-pretreatment. However, it afforded the CO-difference spectrum revealing the peak at 448 nm same as pretreatment with 3-methylcholanthrene (MC). The inhibitory effect of SKF 525-A and 7, 8-benzoflavone on AM demethylation and AN hydroxylation, respectively, in KC-400-induced microsomes also resembled that in microsomes induced by PB plus MC. Further studies using individual PCBs indicated that these compounds were divided into two groups ; namely, 4, 4'-dichlorobiphenyl (DCB), 2, 5, 2', 5'-and 2, 4, 3', 4'-tetrachlorobiphenyl (TCB) were categorized as PB-type, whereas the other group including 3, 4, 3', 4'-TCB, 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB) and 3, 4, 5, 3', 4', 5'-hexachlorobiphenyl (HCB) was categorized as MC-type inducers. Decachlorobiphenyl, the completely chlorinated biphenyl derivative, was found to belong to PB-type. These conclusions were further supported by a spectral study with hexobarbital, which induced type I spectral changes with microsomes from control and 2, 4, 3', 4'-TCB-treated rats, and caused modified type II spectral change with microsomes from 3, 4, 5, 3', 4'-PenCB-treated rats. Considering these results with individual PCBs, it can be assumed that chlorination of both of the para-(4, 4') and two of the meta-positions (3, 3' or 5, 5') of biphenyl is a minimum requirement for the structure to induce cytochrome P-448.

著者

Keita Kohno Junko Kitano Yuta Kohro Hidetoshi Tozaki-Saitoh Kazuhide Inoue Makoto Tsuda

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.41, no.7, pp.1096-1102, 2018-07-01 (Released:2018-07-01)

参考文献数

34

被引用文献数

33

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Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Previous studies have implicated activated microglia in the spinal dorsal horn (SDH) as key cellular intermediaries in neuropathic pain. Microgliosis is among the dramatic cellular alterations that occur in the SDH in models of neuropathic pain established by peripheral nerve injury (PNI), but detailed characterization of SDH microgliosis has yet to be realized. In the present study, we performed a short-pulse labeling of proliferating cells with ethynyldeoxyuridine (EdU), a marker of the cell cycle S-phase, and found that EdU+ microglia in the SDH were rarely observed 32 h after PNI, but rapidly increased to the peak level at 40 h post-PNI. Numerous EdU+ microglia persisted for the next 20 h (60 h post-PNI) and decreased to the baseline on day 7. These results demonstrate a narrow time window for rapidly inducing a proliferation burst of SDH microglia after PNI, and these temporally restricted kinetics of microglial proliferation may help identify the molecule that causes microglial activation in the SDH, which is crucial for understanding and managing neuropathic pain.

著者

Guo-dong Xu Lei Cai Yi-shu Ni Shi-yi Tian Ying-qi Lu Li-na Wang Lian-lian Chen Wen-ya Ma Shao-ping Deng

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.41, no.7, pp.1024-1033, 2018-07-01 (Released:2018-07-01)

参考文献数

54

被引用文献数

16

---

Acarbose and voglibose are the most widely used diabetes drugs as glycosidase inhibitors. In this study, the use of these two inhibitors significantly increased the content of starch in large intestine, and altered the concentration of short-chain fatty acids (SCFAs) by affecting the intestinal microbiota. However, there are some differences in the intestinal microbiome of the two groups of mice, mainly in bacteria such as Bacteroidaceae bacteroides and Desulfovibrionaceae desulfovibrio. The productions of acetate and propionate in caecum in voglibose group were significantly higher than those in acarbose group and two kinds of glycosidase inhibitors were close in the production of butyrate in caecum. The Tax4Fun analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) data indicated that different productions of acetate and propionate between acarbose group and voglibose group may be related to 2-oxoisovalerate dehydrogenase and pyruvate oxidase. In addition, in-vitro experiments suggested that voglibose had less effect on epithelial cells than acarbose after direct stimulation. According to the recent researches of SCFAs produced by intestinal microbiota, our comparative study shown higher concentration of these beneficial fatty acids in the lumen of voglibose-treated mice, which implied a lower level of inflammation.

著者

Jie Hao Wei-Wei Li Hong Du Zhi-Fang Zhao Fan Liu Jing-Chao Lu Xiu-Chun Yang Wei Cui

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.64, no.6, pp.548-557, 2016-06-01 (Released:2016-06-01)

参考文献数

27

被引用文献数

5 31

---

How to provide effective prevention and treatment of myocardial ischemia/reperfusion (I/R) injury and study of the mechanism underlying I/R injury are hotspots of current research. This study aimed to elucidate the effect and cardioprotective mechanism of vitamin C (VC) on myocardial I/R injury. Our study introduced two different I/R models: I/R in vitro and oxygen–glucose deprivation/recovery (OGD/R) in primary neonatal rat cardiac myocytes. We used the mitochondrial permeability transition pore (mPTP) opener lonidamine (LND) and the mitochondrial KATP (mitoKATP) channel inhibitor 5-hydroxydecanoate (5-HD) to analyze the underlying mechanisms. We found that post-treatment with VC decreased I/R injury in our models. Post-treatment with VC significantly decreased I/R-induced injury, attenuated apoptosis, and maintained the functional integrity of mitochondria via alleviation of Ca2+ overload, reactive oxygen species burst, inhibition of the opening of mPTP, and prevention of mitochondrial membrane potential (ΔΨm) depolarization. VC post-treatment increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3β. The present results demonstrate that VC might protect the myocardium from I/R-induced injury by inhibiting the mPTP opening via activation of mitoKATP channels. VC mediates cardioprotection via activation of the phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway. These findings may contribute toward the development of novel strategies for clinical cardioprotection against I/R injury.

著者

Nobuyoshi Kobayashi Koichi Seto Yuki Orikawa Hiroki Hamano Koji Yoshinaga Mineo Takei

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.33, no.2, pp.216-222, 2010-02-01 (Released:2010-02-01)

参考文献数

33

被引用文献数

6 10

---

Z-360 is a novel cholecystokinin (CCK)-2/gastrin receptor antagonist that is being developed for the treatment of pancreatic adenocarcinoma in combination with gemcitabine. A previous study shows that the co-administration of Z-360 with gemcitabine significantly prolonged the survival of mice with orthotopically implanted human pancreatic adenocarcinoma cell lines. To clarify the therapeutic effects of Z-360 in combined with gemcitabine, we analyzed gene expression. When gemcitabine was administered, CCK-2/gastrin receptor expression was induced in an orthotropic xenograft model; the result indicating that Z-360 could act on gemcitabine-sensitive cells. Both in vitro and in vivo studies showed that gemcitabine increased the expression of vascular endothelial growth factor A (VEGFA), a prognostic factor for survival in pancreatic cancer, while Z-360 suppressed this induction of VEGFA gene expression. These results help to explain how Z-360 prolongs survival when used in combination with gemcitabine.

著者

KAZUO OGAWA TADAFUMI TERADA YOSHIYUKI MURANAKA TOSHIHIRO HAMAKAWA SETSURO FUJII

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.10, pp.4130-4136, 1987-10-25 (Released:2009-10-19)

参考文献数

13

被引用文献数

3 4

---

2- (1, t- and c-4-Dialkylcyclohex-r-1-yl) -2-oxoethyl arenesulfonates, 2- (4, 4-dialkylcyclohex-1-yl) -2-oxoethyl arenesulfonates and related compounds were synthesized and evaluated for esteraseand chymotrypsin-inhibitory activities in vitro and for hypolipidemic effect in vivo. The transisomers of 2- (1, 4-dialkylcyclohex-1-yl) -2-oxoethyl arenesulfonates showed much more potent esterase-inhibitory action (about 13 to 6200 times) than the cis-isomers as well as more potent hypolipidemic action (about 1.5 to 10 times) but the chymotrypsin-inhibitory actions of the two isomers were similarly low. On the other hand, the 2-oxoethyl arenesulfonates having a 4, 4- disubstituted cyclohexane ring mostly exhibited potent esterase-inhibitory action (order of IC50; 10-8 to 10-9M) and marked hypolipidemic effect (78% to 95% reductions of plasma triglyceride).

著者

KAZUO OGAWA TADAFUMI TERADA YOSHIYUKI MURANAKA TOSHIHIRO HAMAKAWA SHUNSAKU OHTA MASAO OKAMOTO SETSURO FUJII

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.8, pp.3276-3283, 1987-08-25 (Released:2009-10-19)

参考文献数

19

被引用文献数

5 8

---

trans-and cis-2-Diazo-1- (4-alkylcyclohexyl) -1-ethanones were reacted with arenesulfonic acids to afford the corresponding 2- (4-alkylcyclohexyl) -2-oxoethyl arenesulfonates. The esteraseinhibitory activity and hypolipidemic effect of the arenesulfonates were examined, and it was found that in most cases, the trans-isomers were more active than the corresponding cis-isomers.Stereoselective syntheses of several biologically potent trans-isomers (trans-3) were also developed.

著者

KAZUO OGAWA TADAFUMI TERADA YOSHIYUKI MURANAKA TOSHIHIRO HAMAKAWA SETSURO FUJII

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.6, pp.2426-2436, 1987-06-25 (Released:2009-10-19)

参考文献数

22

被引用文献数

2 4

---

Various ω-cycloalkyl-2-oxoalkyl arenesulfonates were synthesized and evaluated for esterase-and chymotrypsin-inhibitory activities and hypolipidemic activity. Among the tested compounds, 2-oxoalkyl arenesulfonates (4, 8 and 13) having a cyclohexyl substituent at the terminus of the alkyl chain exhibited considerable esterase-inhibitory activity, and several compounds among 4 and 8 also exhibited potent hypolipidemic action. The structure-activity relationships of these compounds are discussed.

著者

小川 和男 寺田 忠史 村中 義幸 浜川 寿博 橋本 貞夫 藤井 節郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.8, pp.3252-3266, 1986-08-25 (Released:2008-03-31)

参考文献数

34

被引用文献数

3 7

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Many 2-oxoalkyl arenesulfonate derivatives having straight or branched alkyl chains of different lengths, 2-oxoalkyl bis-arenesulfonate derivatives, and alkyl arenesulfonate derivatives having a ketal moiety at the 2-position on the alkyl chain were synthesized, and their esterase-inhibitory activities, as well as hypolipidemic activities, were evaluated.Among these compounds, 1-(2, 4, 6-trimethylbenzenesulfonyloxy)-2-dodecanone (III-1u), and 1-(2, 3, 4, 6-tetramethylbenzenesulfonyloxy)-2-hexanone (III-1w), -2-octanone (III-1x) and -2-decanone (III-1y) exhibited potent esterase-inhibitory activities (IC50=3×10-10, 2×10-10, 2×10<-10> and 3×<-11>M, respectively). However, the sulfonate (XV) having a ketal moiety on the alkyl chain and the bis-sulfonate (XVI) exhibited low inhibitory activities toward esterase in comparison with III and XII. Most of the compounds III and some of the compounds XII exhibited potent hypolipidemic activities corresponding to more than 50% lipid-lowering effect (plasma triglyceride and cholesterol ester) in vivo. The structure-activity relatioinships of these compounds are discussed.

著者

小川 和男 寺田 忠史 村中 義幸 浜川 寿博 橋本 貞夫 藤井 節郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.3, pp.1118-1127, 1986-03-25 (Released:2008-03-31)

参考文献数

43

被引用文献数

7 7

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Many 1-substituted 2-alkanone derivatives were synthesized and their inhibitory activities toward pancreatic lipase and esterase were examined in order to obtain hypolipidemic agents. 1-Benzenesulfonyloxy-2-pentanone (VI-2a) and 1-(2, 4, 6-trimethylbenzenesulfonyloxy)-2-pentanone (VI-2q) exhibited not only potent and selective esterase inhibitions (IC50 : 9.0×10-7M and 1.0×10-6M, respectively), but also potent hypolipidemic action (90 and 92% reductions of plasma triglyceride, and 53 and 90% reductions of plasma total cholesterol, respectively). A novel working hypothesis is presented to account for the lowering of the plasma lipids level, i.e., that inhibition of esterase and lipase activities in the small intestinal lumen may be responsible for the decrease in the plasma lipids level.

著者

小川 和男 山田 省三 寺田 忠史 山崎 富生 本邦 隆次

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.33, no.6, pp.2256-2265, 1985-06-25 (Released:2008-03-31)

参考文献数

21

被引用文献数

1 6

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2-Aklylidene-4-arylidene-1, 3-oxathiolan-5-one (III-1a-m) and 2, 4-diarylidene-1, 3-oxathiolan-5-one (III-2a-i) derivatives were synthesized by treating β-aryl-α-mercaptoacrylic acids (I) with alkanoic acid anhydrides (II) or by treating α-acylthio-β-arylacrylic acids (V) with thionyl chloride in dimethylformamide. Basic hydrolysis and methanolysis of III-1 and III-2 in the presence of lithium hydroxide easily occurred to give the corresponding ring-cleaved products, the carboxylic acid (I and II) and the ester (VII and VIII), respectively. The catalytic hydrogenation of the two olefinic bonds of III-2 in the presence of 10% palladium charcoal proceeded easily without ring cleavage to give 1, 3-oxathiolan-5-one (IXa-e) derivatives. The oxidation of III-1 and III-2 with m-chloroperbenzoic acid afforded the corresponding 1, 3-oxathiolan-5-one S-oxide (Xa, b) derivatives.

著者

小川 和男 寺田 忠史 本那 隆次

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.3, pp.930-939, 1984-03-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

5 13

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As a part of our search for new potent analgesic agents, novel fused pyrazole derivatives were synthesized. The reaction of 2-substituted-5-hydroxypyrazole (I) with ethyl 2-substituted (for example COCH3 or CO2C2H5) acylacetates (II) gave mainly pyrazolo [1, 2-a] pyrazole-1, 5 (1H, 5H)-diones (III). On the other hand, similar reaction of I with diethyl benzoylmalonate gave mainly pyrazolo [5, 1-b] [1, 3] oxazin-5 (5H)-one (V) but did not give III at all. Thermal and photochemical isomerization of III gave V. Methanolysis of IIIa in the presence of LiOH occurred with retention of the 4-ethoxycarbonyl-5-pyrazolone ring and similar products (VIa and VIf) were obtained by methanolysis of Va and Vf, respectively. Analgesic activities of the present new compounds were all inferior to that of aminopyrine.

著者

寺田 忠史 藤本 勝彦 野村 誠 山下 純一 小武内 尚 武田 節夫 / 山田 雄次 山口 秀夫 Hideo YAMAGUCHI

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.40, no.10, pp.2720-2727, 1992-10-25 (Released:2008-03-31)

参考文献数

34

被引用文献数

21 27

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Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210).An intact 6, 7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity.The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following : 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.

著者

Maho Nakamura Yoshiki Kuse Kazuhiro Tsuruma Masamitsu Shimazawa Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.40, no.8, pp.1219-1225, 2017-08-01 (Released:2017-08-01)

参考文献数

32

被引用文献数

1 43

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The aim of study was to establish a mouse model of blue light emitting diode (LED) light-induced retinal damage and to evaluate the effects of the antioxidant N-acetylcysteine (NAC). Mice were exposed to 400 or 800 lx blue LED light for 2 h, and were evaluated for retinal damage 5 d later by electroretinogram amplitude and outer nuclear layer (ONL) thickness. Additionally, we investigated the effect of blue LED light exposure on shorts-wave-sensitive opsin (S-opsin), and rhodopsin expression by immunohistochemistry. Blue LED light induced light intensity dependent retinal damage and led to collapse of S-opsin and altered rhodopsin localization from inner and outer segments to ONL. Conversely, NAC administered at 100 or 250 mg/kg intraperitoneally twice a day, before dark adaptation and before light exposure. NAC protected the blue LED light-induced retinal damage in a dose-dependent manner. Further, blue LED light-induced decreasing of S-opsin levels and altered rhodopsin localization, which were suppressed by NAC. We established a mouse model of blue LED light-induced retinal damage and these findings indicated that oxidative stress was partially involved in blue LED light-induced retinal damage.