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 南 慶典 吉田 健一郎 山口 秀夫 山田 雄次 Yuji YAMADA

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.5, pp.907-912, 1993-05-15 (Released:2008-03-31)

参考文献数

58

被引用文献数

6 10

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1-β-Alkyl derivatives of 1-desoxypodophyllotoxin were synthesized, and their cytotoxicity and inhibitory effects on DNA topoisomerase II (Topo-II) and tubulin polymerization were examined.The reaction of epipodophyllotoxin derivatives (1a-c) with trimethylallylsilane in the presence of boron trifluoride etherate gave 1-β-allylated compounds (2a-c). The regiochemistry and the β-stereochemistry of the 1-allyl group were confirmed by comparison of the 13C-NMR spectra and NOE's (%) of 2c, podophyllotoxin (POD) and epipodophyllotoxin (1b). 1-β-Alkyl-1-desoxypodophyllotoxin derivatives (3-8) were prepared from 2b.None of the tested compounds (3-8) showed any inhibitory effect on Topo-II. 1-β-Propyl compound (3) and its 4'-demethyl compound (4) inhibited tubulin polymerization and the cytotoxicities of these compounds were equal to that of VP-16. 1-β-(2, 3-Dihydroxypropyl) compounds (5 and 8) and 1-β-(2, 3-diacetoxypropyl) compounds (6 and 7)showed no inhibitory effect on tubulin polymerization. Although 5 did not inhibit either Topo-II activity or tubulin polymerization, it showed a high cytotoxicity against sarcoma 180.

著者

寺田 忠史 山田 雄次 野村 誠 藤本 勝彦 野村 誠 山下 純一 / 小武内 尚 武田 節夫 南 慶典 吉田 健一郎 山口 秀夫

出版者

公益社団法人日本薬学会

雑誌

CHEMICAL & PHARMACEUTICAL BULLETIN (ISSN:00092363)

巻号頁・発行日

vol.41, no.5, pp.907-912, 1993

被引用文献数

10

---

1-&beta;-Alkyl derivatives of 1-desoxypodophyllotoxin were synthesized, and their cytotoxicity and inhibitory effects on DNA topoisomerase II (Topo-II) and tubulin polymerization were examined.The reaction of epipodophyllotoxin derivatives (1a-c) with trimethylallylsilane in the presence of boron trifluoride etherate gave 1-&beta;-allylated compounds (2a-c). The regiochemistry and the &beta;-stereochemistry of the 1-allyl group were confirmed by comparison of the <SUP>13</SUP>C-NMR spectra and NOE's (%) of 2c, podophyllotoxin (POD) and epipodophyllotoxin (1b). 1-&beta;-Alkyl-1-desoxypodophyllotoxin derivatives (3-8) were prepared from 2b.None of the tested compounds (3-8) showed any inhibitory effect on Topo-II. 1-&beta;-Propyl compound (3) and its 4'-demethyl compound (4) inhibited tubulin polymerization and the cytotoxicities of these compounds were equal to that of VP-16. 1-&beta;-(2, 3-Dihydroxypropyl) compounds (5 and 8) and 1-&beta;-(2, 3-diacetoxypropyl) compounds (6 and 7)showed no inhibitory effect on tubulin polymerization. Although 5 did not inhibit either Topo-II activity or tubulin polymerization, it showed a high cytotoxicity against sarcoma 180.

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 山口 秀夫

出版者

公益社団法人日本薬学会

雑誌

CHEMICAL & PHARMACEUTICAL BULLETIN (ISSN:00092363)

巻号頁・発行日

vol.40, no.10, pp.2720-2727, 1992

被引用文献数

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

寺田忠史 [著]

出版者

[寺田忠史]

巻号頁・発行日

1994

著者

山下 純一 武田 節夫 松本 宏 寺田 忠史 采見 憲男 安本 三治

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.5, pp.2090-2094, 1987-05-25

---

Various O-acyl and N-acyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F_3Thd) were synthesized; namely 5'-O-acyl, 3',5'-di-O-acyl, N^3-acyl, 3',5'-di-O-acetyl-N^3-acyl, 3',5'-di-O-carbamoyl and 3',5'-di-O-ethoxycarbonyl compounds. 5'-O-Acyl derivatives of 2'-deoxy-5-trifluoromethylcytidine were also synthesized. The antitumor activities of these compounds against sarcoma 180 were examined by oral administration to mice. Among the 5'- and 3',5'-diester compounds with aliphatic acids, the 5'-O-hexanoyl compound showed the highest activity. Full protection of the sugar moiety with aroyl or carbamoyl groups considerably decreased the activities, and those of the 3',5'-di-O-m-fluorobenzoyl and 3',5'-di-O-butylcarbamoyl compounds were the smallest. N^3-Benzoyl compounds were slightly more effective than F_3Thd but none of them showed higher activity than the effective O-acyl compounds. In the case of 5'-O-acylates of 2'-deoxy-5-trifluoroniethylcytidine, the 5'-O-benzoyl compound showed the highest activity.

著者

寺田 忠史

出版者

金沢大学

巻号頁・発行日

1984

---

博士論文

著者

寺田 忠史

出版者

東京薬科大学

巻号頁・発行日

1994

---

博士論文

著者

久世 治朗 武藤 俊晴 Konstanty Wierzba 寺田 忠史

出版者

一般社団法人 日本薬物動態学会

雑誌

日本薬物動態学会年会講演要旨集 第19回日本薬物動態学会年会

巻号頁・発行日

pp.295, 2004 (Released:2005-03-03)

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

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

---

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

---

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

---

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

小川 和男 寺田 忠史 本那 隆次

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.3, pp.930-939, 1984-03-25

---

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 COCH_3 or CO_2C_2H_5) 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.