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

上田 享 碓井 博幸 周東 智 井上 英夫

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.9, pp.3410-3416, 1984-09-25 (Released:2008-03-31)

参考文献数

22

被引用文献数

18 24

---

6, 5'-Cyclo-5'-deoxyuridine, a fixed anti form of uridine, was synthesized by a radical cyclization of 5'-bromo (or iodo)-5'-deoxy-2', 3'-O-isopropylidene-5-chloro (or bromo)-uridine with tri-■-butyltin hydride followed by dehydrohalogenation and deacetonation. The 5-bromo and 4-thio derivatives of the cyclouridine were also prepared and were converted to the 2', 3'-cyclic phosphates. These nucleotides were hydrolyzed by pancreatic ribonuclease. The result showed that the enzyme recognizes the pyrimidine nucleotides in the anti form. 6, 5'-Cyclo-5'-deoxycytidine was also synthesized by two routes.

著者

佐野 友春 井上 英夫 上田 亨

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.9, pp.3595-3598, 1985-09-25 (Released:2008-03-31)

参考文献数

15

被引用文献数

6 10

---

2'-Deoxy-6, 2'-methano-cyclouridine, a carbon-bridged cyclonucleoside fixed in a high-anti conformation, was synthesized. Treatment of a 3', 5'-O-protected 6-cyano-2'-O-imidazolythiocarbonyluridine with tri-n-butyltin hydride afforded a 6, 2'-oxomethano-cyclouridine derivative in low yield. Base treatment of 5-bromo-2'-deoxy-2' (S)-ethoxycarbonylmethyl-3', 5'-O-(tetraisopropyldisiloxane-1, 3-diyl) uridine resulted in an intramolecular Michael reaction followed by dehydrobromination to give the 6, 2'-cyclonucleoside. The latter was de-ethoxycarbonylated by treatment with sodium chloride and water in dimethylsulfoxide followed by desilylation to furnish the title compound.

著者

佐野 友春 周東 智 井上 英夫 上田 亨

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.9, pp.3617-3622, 1985-09-25 (Released:2008-03-31)

参考文献数

7

被引用文献数

25 41

---

The reaction of methylenetriphenylphosphorane with 2'-keto-3', 5'-O-(tetraisopropyldisiloxane-1, 3-diyl) uridine afforded the 2'-methyleneuridine (1). Oxidation of 1 with osmium tetroxide and tert-butyl hydroperoxide or N-methylmorpholine-N-oxide afforded a mixture of a 2'-hydroxymethyluridine (2) and its arabinosyl isomer. Oxidation at lower temperature gave the former as the main product. Compound 2 was converted to the 5-bromo-2'-iodomethyl derivative (3) through the 2'-mesyloxy compound, and 3 was treated with tri-n-butyltin hydride to give the 6, 2'-methano-cyclo-5, 6-dihydro derivative (4). Compound 4 was dehydrobrominated and deprotected to furnish 6, 2'-methano-cyclouridine, a uridine fixed in high-anti conformation. Some results on the synthesis and cleavage of the 2'-spiro-epoxy derivative prepared from the 2'-ketouridine are also presented.

著者

碓井 博幸 上田 亨

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.4, pp.1518-1523, 1986-04-25 (Released:2008-03-31)

参考文献数

10

被引用文献数

12 16

---

Treatment of 3', 5'-O-(tetraisopropyldisiloxane-1, 3-diyl)-2'-ketoadenosine (1) with methylenetriphenylphosphorane gave the 2'-methylene derivative (2). Hydroxylation of 1 with OsO4 gave the 2'-hydroxymethyladenosine (4), which was then converted to the 2'-phenylthiomethyl derivative (5). Photocyclization followed by deprotection of the product furnished 8, 2'-methanoadenosine (7), and adenosine fixed in a high-anti conformation. Oxidation of a 2'-hydroxyethylideneadenosine with OsO4 gave the 2'-dihydroxyethyladenosine (10), which was also converted to the 2'-(2-phenylthioethyl) derivative (11). The photocyclization of 11 and successive elimination of the hydroxyl group gave the 8, 2'-ethenoadenosine (13). Catalytic hydrogenation and deprotection of 13 afforded 8, 2'-ethanoadenosine (15). The circular dichroism spectral features of C-cycloadenosine are discussed.

著者

碓井 博幸 松田 彰 上田 亨

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.5, pp.1961-1967, 1986-05-25 (Released:2008-03-31)

参考文献数

12

被引用文献数

5 7

---

Guanosine fixed in the high-anti conformation by means of an 8, 2'-methylene bridge was prepared. N2-Acetyl-O6-ethylguanosine (2) was converted to the 3', 5'-O-(tetraisopropyldisiloxane-1, 3-diyl) derivative (3). Oxidation of 3 to the 2'-keto derivative (4) and successive coupling with methylenetriphenylphosphorane gave the 2'-methylidene derivative (5) and its α-anomer. The 2'-methylidene function of 5 was hydroxylated, and the 2'-hydroxymethyl group was modified to give the phenylthiomethyl derivative (6). Photocyclization of 6 followed by deprotection of the sugar and base protecting groups furnished 8, 2'-methanoguanosine (12). The alpha anomer of 12 was likewise prepared. The circular dichroism spectra of 12, its α-anomer, and related compounds were measured.

著者

佐野 友春 上田 亨

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.1, pp.423-425, 1986-01-25 (Released:2008-03-31)

参考文献数

13

被引用文献数

10 11

---

The synthesis of 6, 3'-methanouridine was achieved by condensation of 2, 4-dimethoxy-6-lithiomethylpyrimidine with 5-O___--(tert-butyldi-methyl)silyl-1, 2-O___--isopropylidene-3-ketoxylose, followed by intramolecular glycosylation and deprotection. 6, 3'-Methanocytidine was also prepared from the 4-O___--methyl intermediate. The title compounds are the first example of uridine and cytidine fixed between C-6 and the 3'-position of pyrimidine nucleosides by a methylene group.

著者

松田 彰 渡辺 一之 宮坂 貞 上田 亨

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.37, no.2, pp.298-303, 1989-02-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

3 5

---

The synthesis of a new carbon-bridged cyclopurine nucleoside, 2'-deoxy-8, 2'-methanoguanosine (25), which is fixed in a high-anti torsional angle region, was accomplished. 2-Acetamido-6-ethoxy-8-methanesulfonyl-9-(3, 5-di-O-acetyl-2-O-tosyl-1-β-D-ribofuranosyl)purine (18) was cyclized with carbanions of malonic esters, followed by sequential deblocking and decarboxylation to afford 25. The ultraviolet spectra of 25 in neutral solution revealed two separated bands corresponding to their B1u and B2u transitions, which was rather similar to the case of its O6-ethyl derivative (22), but quite different from the previously reported 8, 2'-methanoguanosine (26), a ribosyl counterpart of 25. The circular dichroism spectra of these cyclonucleosides are also discussed.

著者

山下 純一 松本 宏 小林 和弘 野口 和春 安本 三治 上田 亨

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.37, no.9, pp.2287-2292, 1989-09-25 (Released:2008-03-31)

参考文献数

30

被引用文献数

7 15

---

A practical synthesis of 3'-O-benzyl-2'-deoxy-5-trifluoromethyluridine (1), a candidate antitumor agent for clinical testing, was developed from 2'-deoxy-5-iodouridine (3). Benzylation of 2'-deoxy-5-iodo-5'-O-trityluridine (14) with benzyl bromide and sodium hydride in tetrahydrofuran gave the 3'-O-derivative (16). Benzoylation of 16 afforded the N3-benzoyl derivative (17). Coupling of 17 with trifluoromethylcopper, prepared from bromotrifluoromethane and copper powder in the presence of 4-dimethylaminopyridine, gave the 5-trifluoromethyl derivative (19) minimally contaminated with the 5-pentafluoroethyl compound. Deprotection of 19 furnished 1.

著者

JUN-ICHI YAMASHITA SETSUO TAKEDA HIROSHI MATSUMOTO NORIO UNEMI MITSUGI YASUMOTO

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.2373-2381, 1987-06-25 (Released:2009-10-19)

参考文献数

12

被引用文献数

3 3

---

Various O-alkoxyalkyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F3Thd) were synthesized, and the antitumor activities of the compounds against sarcoma 180 were examined by oral administration to mice. Among the formal-type derivatives, 3', 5'-di-O-ethoxymethyl (3), 3', 5'-di-O-benzyloxymethyl (12), 5'-O-benzyloxymethyl (13) and 3'-O-benzyloxymethyl (14) compounds showed high activities, which were six-fold higher than that of F3Thd itself. Since acetal-type derivatives were unstable under acidic conditions, antitumor testing of the compounds was also carried out with co-administration of sodium bicarbonate. 5'-O- (1-Ethoxypropyl) -F3Thd (25) and 5'-O- (1-benzyloxypropyl) -F3Thd (37) showed the highest activities among the acetal-type derivatives, but the ED50 values of the compounds were not lower than those of effective formal-type compounds.These O-alkoxyalkyl derivatives of F3Thd are resistant to degradation by thymidine phosphorylase and are activated by microsomal drug-metabolizing enzymes after absorption.

著者

渋谷 進 国中 明 吉野 宏

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.22, no.3, pp.719-721, 1974-03-25 (Released:2008-03-31)

被引用文献数

16 20

著者

兼松 顯 吉安 貴史 吉田 光孝

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.38, no.5, pp.1441-1443, 1990-05-25 (Released:2008-03-31)

参考文献数

8

被引用文献数

7 10

---

The stereochemistry of the title compound 3 was confirmed by X-ray analysis. The 6-acetylthio derivatives with an OH group at C-14 were also designed and synthesized.

著者

HIROYUKI NAGANO YOSHIHARU NAWATA MASATOMO HAMANA

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.4068-4077, 1987-10-25 (Released:2009-10-19)

参考文献数

17

被引用文献数

6 12

---

In order to elucidate the mechanism of the 2-acetylation in the reaction of nicotinic acid 1-oxide (2a) with boiling acetic anhydride, thermal reactions and reactions with hot acetic anhydride have been explored with 3-X-pyridine 1-oxides (2). The former reactions of 2d (X =CONHAc), 2f (X = CONMeAc), 2h (X = CH2OAc) and 2j [X = CH (OAc) 2] result in recovery or decomposition. The latter reactions of 2c (X =CONH2), 2d, 2e (X =CONHMe), 2h and 2j bring about mainly deoxygenative α-acetoxylation, no 2-acetylation being noticed. However, the reaction of 2f with acetic anhydride affords 6, 7-dihydro-6-methyl-7-methylene-5H-pyrrolo [3, 4-b] pyridin-5-one 1-oxide (7) as an initial product, which further undergoes deoxygenative β-acetoxylation to give 7-acetoxy-7-acetoxymethyl-6, 7-dihydro-6-methyl-5H-pyrrolo [3, 4-b] pyridin-5-one (8) and 7-acetoxymethylene-6, 7-dihydro-6-methyl-5H-pyrrolo [3, 4-b] pyridin-5-one (9). On the basis of these results we propose a new electrophilic pathway for the 2-acetylation of 2a and 2f.

著者

菅田 節朗 山之内 正子 松島 美一

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.25, no.5, pp.884-889, 1977-05-25 (Released:2008-03-31)

被引用文献数

20 30

---

Three isomers of meso-tetrapyridylporphins, i. e. tetra (2-pyridyl)-(2), (3-pyridyl)-(3), and (4-pyridyl)-(4), porphin have been synthesized. They were soluble in acetic acid, chloroform and acidic aqueous solvents. Solubilities in chloroform, dimethylformamide and pyridine were in the order 3>2>4. Comparison of the visible spectra indicated that the intensities of the bands due to 0-0 transitions decreased (3>4>2) with an increase of the electron-withdrawing character of the pyridyl substituent. The copper (II) and zinc (II) complexes of 2 and 3 have been prepared. Infrared and nuclear magnetic resonance spectra and their assignments of the porphins and/or the metal complexes were described.

著者

河野 彬 菅田 節朗 原 泰寛 田中 睦子 加留部 喜晴 松島 美一

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.5, pp.1666-1669, 1983-05-25 (Released:2008-03-31)

参考文献数

19

被引用文献数

2

---

A sensitive method for the assay of pyrimidine nucleoside phosphorylases in preparations of human and animal tissues by determination of pyrimidines is described. Pyrimidines formed enzymatically from thymidine, uridine, 5-fluorouridine, and 5'-deoxy-5-fluorouridine are determined by means of high-performance liquid chromatography with ultraviolet (UV) detection. The pyrimidines, after extraction with ethyl acetate, are separated by reversed-phase chromatography on μ-Bondapak C-18/Porasil. The limits of detection are 2.5, 1.0, and 2.0 pmol for thymine, uracil, and 5-fluorouracil, respectively.

著者

河野 彬 原 泰寛 菅田 節朗 松島 美一 上田 亨

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.5, pp.1919-1921, 1984-05-25 (Released:2008-03-31)

参考文献数

15

被引用文献数

12 16

---

A thymidine phosphorylase preparation was partially purified from human liver tumor tissues (poorly differentiated adenocarcinoma). The substrate specificity of the enzyme was investigated with eleven pyrimidine nucleosides. Thymidine and 2'-deoxyuridine were good substrates, while uridine, 3'-deoxyuridine, 5'-deoxyuridine, and 2', 3'-dideoxy-3'-hydroxy-methyluridine were not. Uridines substituted at the 5-position by a cyano, bromo, or chloro group were also phosphorolyzed by the enzyme, but the activity for 5-fluorouridine was much lower. 5'-Deoxy-5-fluorouridine was also cleaved. Either a 5-substituent or a 2'-deoxy structure seems to be essential for a good substrate.

著者

河野 彬 原 泰寛 菅田 節朗 加留部 善晴 松島 美一 石塚 秀夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.1, pp.175-178, 1983-01-25 (Released:2008-03-31)

参考文献数

20

被引用文献数

77 93

---

Activities of pyrimidine nucleoside phosphorylases were assayed in extracts of human tumors, normal tissues of the same organs and tumors of mice (Sarcoma-180) and guinea pigs (Line-10), with thymidine (dThd), uridine (Urd), and 5'-deoxy-5-fluorouridine (5'-DFUR) as substrates. The nucleoside cleaving activities were higher in extracts of human tumor tissues than in those of normal tissues of the same organs. In human tissues, phosphorolytic activitiy towards dThd was high, while that towards Urd was low. In animal tumors, Urd was the best substrate. 1-(2'-Deoxy-β-D-glucopyranosyl)-thymine (GPT), a specific inhibitor of uridine phosphorylase, inhibited the phosphorolysis of Urd and 5'-DFUR in extracts of animal tumors, but not that of dThd and 5'-DFUR in extracts of human tumors. A thymidine phosphorylase preparation was partialy purified from human lung cancer. Km values of the preparation were 2.43×10-4 M and 1.69×10-3 M for dThd and 5'-DFUR, respectively. We conclude that in human tumors a thymidine phosphorylase activity converts 5'-DFUR to 5-fluorouracil, an activated form.

著者

菅田 節郎 河野 彬 原 泰寛 加留部 善晴 松島 美一

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.1219-1222, 1986-03-25 (Released:2008-03-31)

参考文献数

16

被引用文献数

5 11

---

A thymidine phosphorylase (TP) preparation was partially purified from human gastric cancer (poorly differentiated adenocarcinoma). The specific activity of the final preparation represented a 379-fold purification of the 7000g supernatant of tissue homogenate. The phosphorolytic activities toward thymidine (dThd), 5'-deoxy-5-fluorouridine (5'-DFUR), and 1-(tetrahydro-2-furanyl)-5-fluorouracil (Tegafur) remained closely in parallel during the whole purification procedure. The results provide evidence in support of the assumption that 5'-DFUR and Tegafur are converted into 5-fluorouracil, an activated form of the antitumor agents, in humn tumor tissues by a TP activity. The values of Km of the TP preparation were 1.68×10-4, 1.72×10-3, 1.33×10-2, and 4.76×10-2M for dThd, 5'-DFUR, Tegafur, and uridine, respectively.