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

Miwa NISHIDA Ayako HINO Kazushige MORI Takehisa MATSUMOTO Takashi YOSHIKUBO Hideo ISHITSUKA

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.19, no.11, pp.1407-1411, 1996-11-15 (Released:2008-04-10)

参考文献数

20

被引用文献数

87 100

---

The antitumor activity of cytostatic 5'-deoxy-5-fluorouridine (5'-dFUrd) depends on its being converted to 5-fluorouracil (5-FUra) by the enzyme thymidine phosphorylase (dThdPase, EC 2.4.2.4). We prepared mouse anti-human dThdPase monoclonal antibodies to serve as tools for clinical studies with this drug. Partially purified dThdPase obtained from HCT116 human colon cancer cells grown in athymic mice was used as an antigen for the immunization of mice. Six hydridomas were cloned which produced anti-human dThdPase antibodies, as detected by Western blot analysis with human dThdPase. With these antibodies, we developed an ELISA method sensitive enough to measure dThdPase levels, even in tumor tissue samples weighing as little as 10 mg. In addition, one monoclonal antibody was suitable for immunologically staining the enzyme in tumor tissues. Thus, these anti-human dThdPase monoclonal antibodies could be used to measure levels of the enzyme in tumor cells, which is essential for the activation of 5'-dFUrd.

著者

Tohru ISHIKAWA Yu FUKASE Taeko YAMAMOTO Fumiko SEKIGUCHI Hideo ISHITSUKA

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.21, no.7, pp.713-717, 1998-07-15 (Released:2008-04-10)

参考文献数

19

被引用文献数

28 39

---

Capecitabine (N4-pentyloxycarbonyl-5'-fluorocytidine) is a novel fluoropyrimidine carbamate that was synthesized for the purpose of finding antitumor drugs with improved safety and efficacy profiles compared with those of 5-fluorouracil (5-FUra) and doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUrd). The present study compared the antitumor activities of the compound with those of other fluoropyrimidines in 12 human cancer xenograft models and their antimetastatic activities in murine tumor models. The antitumor efficacy of capecitabine was greater than those of 5'-dFUrd, UFT (a mixture of tegafur and uracil) and 5FUra. Capecitabine was also much safer, particularly much less toxic to the intestinal tract, than the other compounds, indicating higher therapeutic indices. The therapeutic indices. The therapeutic indices of capecitabine, 5'-dFUrd and 5-FUra were >40, >20 and 2.0 against the human CXF280 colon cancer xenograft, the most sensitive line to the fluoropyrimidines so far tested, and 5.1, 1.5, and <1.5 against the human HCT116 colon cancer xenograft with ordinary sensitivity, respectively. In addition, capecitabine, as well as 5'-dFUrd, selectively suppressed the spontaneous metastasis of mouse Lewis lung carcinoma in mice at extremely low doses, 32-64 fold lower than their minimum effective dose (MED) against the primary tumor growth. Capecitabine was even more antimetastatic than 5'-dFUrd. These results indicate that dapecitabine has high therapeutic potential.

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.

著者

IKUO ADACHI TERUO YAMAMORI YOSHIHARU HIRAMATSU KATSUNORI SAKAI SHIN-ICHI MIHARA MASARU KAWAKAMI MASAO MASUI OSAMU UNO MOTOHIKO UEDA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.36, no.11, pp.4389-4402, 1988-11-25 (Released:2011-02-08)

参考文献数

19

被引用文献数

31 49

---

A series of 4-aryl-4, 7-dihydrothieno [2, 3-b] pyridine-5-carboxylate derivatives (I) was synthesized and tested for binding affinity to Ca2+ channels in rat cerebral cortex membranes, coronary vasodilator effect in isolated guinea pig hearts, and antihypertensive activity in spontaneously hypertensive rats.Several compounds had potent coronary vasodilator and antihypertensive activities.The structure-ctivity relationships of the series indicated that a lipophilic 3-alkyl substituent with moderate bulkiness was effective for enhancing the pharmacological potencies.Among them, methyl 4, 7-dihydro-3-isobuty1-6-methy1-4-(3-nitrophenyl) thieno [2, 3-b] pyridine-5-carboxylate (S-312) was selected as a promising cardiovascular agent.The relationship between the absolute configuration of S-312 and its biological activities is also presented.