著者

岡村 裕 藤井 節郎 河内 卓 川波 寿 桑野 信彦 山村 雄一

出版者

The Japanese Cancer Association

雑誌

GANN Japanese Journal of Cancer Research (ISSN:0016450X)

巻号頁・発行日

vol.53, no.4, pp.365-370, 1962 (Released:2008-10-23)

参考文献数

18

被引用文献数

1

---

A basic protein fraction having toxohormone activities, isolated from rat Rhodamine sarcoma, was subjected to enzymatic hydrolysis with trypsin, pepsin, and pronase, resulting in the splitting of 12.3%, 19.1%, and 57.4% of peptide bonds of the basic protein respectively.The effect of the hydrolysis on the toxohormone activities of the basic protein was determined by bioassay with rats or mice. Liver catalase depression was markedly diminished by hydrolysis with pronase and pepsin but not by trypsin. Plasma iron decrease was affected by none of these enzymes. Liver tryptophan pyrrolase depression was markedly diminished by hydrolysis with any one of these enzymes.These results suggest that these three different activities of toxohormone are associated with different chemical entities of the basic protein.

著者

丸中 照義 南 慶典 梅野 幸彦 安田 昭男 佐藤 俊幸 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.28, no.6, pp.1795-1803, 1980-06-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

7 6

---

Four metabolites of the antitumor agent 1-(tetrahydro-2-furanyl)-5-fluorouracil, formed in vitro by rat liver microsomes, were isolated by thin-layer chromatography or high-performance liquid chromatography. On the basis of mass spectrometry, 1H-NMR spectral analysis, and comparison with authentic samples, these metabolites were identified as 1-(trans-4-hydroxytetrahydro-2-furanyl)-5-fluorouracil, 1-(cis-4-hydroxytetrahydro-2-furanyl)-5-fluorouracil, 1-(trans-3-hydroxytetrahydro-2-furanyl)-5-fluorouracil and 1-(4, 5-dehydrotetrahydro-2-furanyl)-5-fluorouracil. These metabolites were also found in the plasma and urine of rats after administration of 1-(tetrahydro-2-furanyl)-5-fluorouracil.

著者

廣橋 満 木戸 勝 山本 栄仁 小島 裕 實川 浩一郎 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.41, no.9, pp.1498-1506, 1993-09-15 (Released:2008-03-31)

参考文献数

23

被引用文献数

6 10

---

The reactivities of 5-fluorouracil (5-FUra) degradation inhibitors, 2, 4- (2) and 2, 6-dihydroxypyridines (3), were investigated. Acylation of 2 and 2, 4-bis(trimethylsilyloxy)pyridines with equimolar amounts of acid chlorides preferentially occurred at the 4-OH and 2-OH positions, respectively, and the structure of monobenzoylated 5-chloro-2, 4-dihydroxypyridine (2b) was determined as 4-benzoyloxy-5-chloro-2-pyridone (5b) by X-ray crystallo-graphic analysis. Compounds 2 and 3, as well as the N-2-tetrahydrofuryl (11), N-alkyl (12), and N-carbamoyl (14) derivatives of 2, exhibit dynamic keto-enol tautomerism. The acyl derivatives of these pyridines are labile and are thought to be active esters. Monoacyl ester derivatives of these pyridines were combined with 5-FUra analogs to develop novel antitumor agents containing an inhibitor of 5-FUra degradation. One of them, 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil (BOF-A2) (22b), was the most effective and is currently undergoing late phase-II clinical trials.

著者

藤井 節郎 奥田 拓道 赤沢 明 安田 行寛 川口 安郎 福永 育史 西川 栄郎

出版者

公益社団法人日本薬学会

雑誌

薬学雑誌 (ISSN:00316903)

巻号頁・発行日

vol.95, no.6, pp.732-740, 1975

被引用文献数

5

---

In order to investigate the fate of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) in comparison with that of 5-fluorouracil tritiated FT-207 (<SUP>3</SUP>H-FT-207) and 5-fluovouracil (<SUP>3</SUP>H-5-fluorouracil)were administered from the rectum in normal and AH-130 tumor-bearing rats, and rapid absorption of <SUP>3</SUP>H-FT-207 or <SUP>3</SUP>H-5-fluorouracil, was observed. Blood level of radioactivity after rectal administration of <SUP>3</SUP>H-FT-207 was higher and more continuous than that of <SUP>3</SUP>H-5-fluorouracil. Although the radioactivity after rectal administration of <SUP>3</SUP>H-FT-207 and <SUP>3</SUP>H-5-fluovouracil was widely distributed in the various tissues of the animal with or without tumor, the highest concentration of the radioactivity was observed in the kidneys, and higher in tumor. The radioactivity in lymphatic gland reached a maximum level within 2-4 hr after the rectal administration of <SUP>3</SUP>H-FT-207 and declined very slowly. The urinary excretion of radioactivity within 24 hr was about 30% of the administered dose of <SUP>3</SUP>H-FT-207. More than 85% of the excreted radioactivity accounted for FT-207 and its metabolite, &alpha;-fluoro-&beta;-alanine. Other metabolites such as 5-fluorouracil, &alpha;-fluoro-&beta;-ureidopropionic acid and tritiated water were detected in small amounts in rat urine. The radioactivity in blood and tumor, 4 hr after rectal administration of <SUP>3</SUP>H-FT-207, was found to represent FT-207. However, the radioactivity in liver was due to the presence of &alpha;-fluoro-&beta;-alanine. About 90% radioactivity in lymphatic gland within 2-6 hr after rectal administration of <SUP>3</SUP>H-FT-207 was detected as FT-207.

著者

采見 憲男 武田 節夫 北里 健二 梶原 大義 藤井 節郎

出版者

公益社団法人 日本化学療法学会

雑誌

CHEMOTHERAPY (ISSN:00093165)

巻号頁・発行日

vol.26, no.2, pp.200-208, 1978-03-25 (Released:2011-03-08)

参考文献数

13

---

The antitumor activity of 1, 3-Bis (tetrahydro-2-furanyl) -5-fluoro-2, 4-pyrimidinedione (FD-1) was compared with that of 1- (2-Tetrahydrofuryl) -5-fluorouracil (FT) or 5-Fluorouracil (5-FU) in a number of tumor systems.FD-1 had significant activity against the solid forms but not the ascitic forms, and it produced a greater inhibition in tumor growth than FT. On AH 130 solid form, the therapeutic index (LD50/ED50) of FD-1 and FT were respectively 18. 3 and 10.6.FD-1 was evaluated against the ip and sc implanted L 1210 leukemia by single, intermittent or daily administration. FD-1 retained some degree of antileukemic activity against the ic implanted L 1210.No significant difference in antitumor activity was observed between the R and S isomers or the racemic mixture (FD-1).A higher activity of FD-1 compared to FT was possibly due to the increased 5-FU level in tumor through its metabolite, 3- (tetrahydro-2-furanyl) -5-fluoro-2, 4-pyrimidinedione (3-FT).

著者

藤井 節郎 中村 芳正 武田 節夫 森田 健一 佐藤 俊幸 丸中 照義 川口 安郎 采見 憲男

出版者

The Japanese Cancer Association

雑誌

GANN Japanese Journal of Cancer Research (ISSN:0016450X)

巻号頁・発行日

vol.71, no.1, pp.30-44, 1980-02-29 (Released:2008-10-23)

参考文献数

14

---

The metabolism, antitumor activity, and acute toxicity of 5-fluoro-1, 3-bis-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FD-1) were investigated in animals, compared with 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FT). It was found that after oral administration of FD-1, the level of 5-fluorouracil (5-FU) was maintained higher and longer than after administration of FT, and that a large amount of 5-FU was released from FD-1 by liver microsomal drugmetabolizing enzymes or spontaneous hydrolysis via 5-fluoro-3-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (3-FT) and FT. FD-1 had a significant activity against the solid form of Ehrlich carcinoma, sarcoma-180, hepatoma AH130, Yoshida sarcoma, Walker carcinosarcoma-256, and leukemia L1210 and P388, but not the ascitic forms, and it produced greater inhibition of tumor growth than FT. The acute toxicity of FD-1 was less than that of FT.

著者

横尾 信夫 佐藤 文泰 桐原 順子 横山 融 池ケ谷 耕司 永倉 正彦 藤井 節郎

出版者

一般社団法人 日本臨床化学会

雑誌

臨床化学 (ISSN:03705633)

巻号頁・発行日

vol.14, no.1, pp.8-12, 1985-02-25 (Released:2012-11-27)

参考文献数

13

被引用文献数

1

---

The effect of chymotrypsin inhibitors on the intestinal absorption of insulin was investigated in conscious and unrestrained rabbits. Insulin at a dose of 25U/kg with 10mg/kg of chymotrypsin inhibitors was administered intraduodenally via an indwelled catheter. The blood glucose level was decreased following an administration of insulin in combination with each chymotrypsin inhibitor. The order of the effect on the intestinal absorption was related with the order of chymotrypsin inhibitory activity. Maximal decrease was observed when insulin was administered with such a strong inhibitor as FK 448, [4-(4-isopropylpipe-radinocarbonyl) phenyl 1, 2, 3, 4-tetrahydro-1-naphthoate methanesulfonate], whose IC50 value was 7×10-7M, and the decrease of the glucose level was 25%, compared with the level before administration. The effect of inhibitors which inhibit both chymotrypsin and trypsin was almost the same with that of chymotrypsin specific inhibitors.

著者

横尾 信夫 服部 英三 平田 光輝 渡辺 好一郎 佐藤 文泰 永倉 正彦 藤井 節郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.107, no.9, pp.732-737, 1987-09-25 (Released:2008-05-30)

参考文献数

9

被引用文献数

1 1

---

Synthesis of water-soluble chymotrypsin specific inhibitors was attempted to study the roles of chymotrypsin-like enzymes in vivo. Previously we reported that the esters of carboxylic acid containing a condensed ring showed stronger activity than those containing a single ring system. Then we synthesized 4-substituted phenyl esters of carboxylic acid containing a condensed ring, such as tetralin, naphthalene, indole etc., and their inhibitory activities were compared. Among these compounds, esters of tetralin-1-carboxylic acid (FK-448) and 1-naphthylacetic acid showed the strongest activity, and their IC50 values were 8×10-7, 5×10-7 M, respectively. Tetralin-2-carboxylate and 2-naphthylacetate inhibited weaker than 1-analogues. Esters of basic quinoline carboxylic acid and bulky carboxylic acids containing a three-ring system inhibited poorly. Chymotrypsin produced equimolecular 4-substituted phenol rapidly and thereafter the amount of 4-substituded phenol increased slowly, when incubated with FK-448 at 37°C.

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

---

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

---

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

藤井 節郎 奥田 拓道 赤沢 明 安田 行寛 川口 安郎 福永 育史 西川 栄郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.95, no.6, pp.732-740, 1975-06-25 (Released:2008-05-30)

参考文献数

13

被引用文献数

4 5

---

In order to investigate the fate of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) in comparison with that of 5-fluorouracil tritiated FT-207 (3H-FT-207) and 5-fluovouracil (3H-5-fluorouracil)were administered from the rectum in normal and AH-130 tumor-bearing rats, and rapid absorption of 3H-FT-207 or 3H-5-fluorouracil, was observed. Blood level of radioactivity after rectal administration of 3H-FT-207 was higher and more continuous than that of 3H-5-fluorouracil. Although the radioactivity after rectal administration of 3H-FT-207 and 3H-5-fluovouracil was widely distributed in the various tissues of the animal with or without tumor, the highest concentration of the radioactivity was observed in the kidneys, and higher in tumor. The radioactivity in lymphatic gland reached a maximum level within 2-4 hr after the rectal administration of 3H-FT-207 and declined very slowly. The urinary excretion of radioactivity within 24 hr was about 30% of the administered dose of 3H-FT-207. More than 85% of the excreted radioactivity accounted for FT-207 and its metabolite, α-fluoro-β-alanine. Other metabolites such as 5-fluorouracil, α-fluoro-β-ureidopropionic acid and tritiated water were detected in small amounts in rat urine. The radioactivity in blood and tumor, 4 hr after rectal administration of 3H-FT-207, was found to represent FT-207. However, the radioactivity in liver was due to the presence of α-fluoro-β-alanine. About 90% radioactivity in lymphatic gland within 2-6 hr after rectal administration of 3H-FT-207 was detected as FT-207.

著者

川口 安郎 中村 芳正 佐藤 俊幸 武田 節夫 丸中 照義 藤井 節郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.98, no.4, pp.525-536, 1978-04-25 (Released:2008-05-30)

参考文献数

14

被引用文献数

5 8

---

After oral administration of 5-fluoro-1, 3-bis (tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FD-1), the level of 5-fluoro-2, 4-pyrimidinedione (5-FU) was 5 to 7 times higher in the plasma and normal tissues and 8 to 12 times in tumor tissue than after administration of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FT). Moreover, these levels were maintained longer than after administration of FT. In tumor tissue, the concentration of 5-FU was still as high as 1.42 μg/g 12 hr after administration of FD-1. FD-1 was degraded to 5-fluoro-3-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (3-FT) by liver microsomal drug-metabolizing enzymes in vitro and to FT spontaneously. Subsequently, FT was converted enzymically to the active substance, 5-FU, and 3-FT changed to 5-FU spontaneously. Conversion of FD-1 to 5-FU via 3-FT was greater than via FT. It is concluded that a large amount of 5-FU formed after administration of FD-1 is formed via 3-FT. γ-Hydroxybutyric acid was found to be formed in vivo and in vitro from the tetrahydrofuranyl group of FD-1.

著者

中山 豊男 平良 盛三 池田 昌人 芦澤 広 織田 実 荒川 勝雅 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.41, no.1, pp.117-125, 1993-01-15 (Released:2008-03-31)

参考文献数

15

被引用文献数

5 10

---

By developing 6-amidino-2-naphthyl 4-guanidinobenzoate (I, FUT-175) as a basic structure, its various derivatives were synthesized and their inhibitory activities on trypsin, plasmin, kallikrein, thrombin, C1^- and C1s^- as well as on complement-mediated hemolysis were examined. The protective effect of these compounds on complement-mediated Forssman shock was also examined in guinea pigs. 6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]-benzoate (41, FUT-187) was found to be a suitable compound for oral administration with anti-complement activity superior to that of compound I.

著者

川口 安郎 中村 芳正 佐藤 俊幸 武田 節夫 丸中 照義 藤井 節郎

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.98, no.4, pp.525-536, 1978

被引用文献数

8

---

After oral administration of 5-fluoro-1, 3-bis (tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FD-1), the level of 5-fluoro-2, 4-pyrimidinedione (5-FU) was 5 to 7 times higher in the plasma and normal tissues and 8 to 12 times in tumor tissue than after administration of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FT). Moreover, these levels were maintained longer than after administration of FT. In tumor tissue, the concentration of 5-FU was still as high as 1.42 &mu;g/g 12 hr after administration of FD-1. FD-1 was degraded to 5-fluoro-3-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (3-FT) by liver microsomal drug-metabolizing enzymes in vitro and to FT spontaneously. Subsequently, FT was converted enzymically to the active substance, 5-FU, and 3-FT changed to 5-FU spontaneously. Conversion of FD-1 to 5-FU via 3-FT was greater than via FT. It is concluded that a large amount of 5-FU formed after administration of FD-1 is formed via 3-FT. &gamma;-Hydroxybutyric acid was found to be formed in vivo and in vitro from the tetrahydrofuranyl group of FD-1.