著者

Kazuma Kaitoh Aki Nakatsu Shuichi Mori Hiroyuki Kagechika Yuichi Hashimoto Shinya Fujii

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.67, no.6, pp.566-575, 2019-06-01 (Released:2019-06-01)

参考文献数

33

被引用文献数

9

---

We report here the development of phenylamino-1,3,5-triazine derivatives as novel nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are promising candidates for clinical treatment of multiple diseases. By using the phenylamino-1,3,5-triazine scaffold as a template structure, we designed and synthesized a series of 4-cyanophenylamino-1,3,5-triazine derivatives. The synthesized compounds exhibited PR antagonistic activity, and among them, compound 12n was the most potent (IC50 = 0.30 µM); it also showed significant binding affinity to the PR ligand-binding domain. Docking simulation supported the design rationale of the compounds. Our results suggest that the phenylamino-1,3,5-triazine scaffold is a versatile template for development of nonsteroidal PR antagonists and that the developed compounds are promising lead compounds for further structural development of nonsteroidal PR antagonists.

著者

浜田 康正 水野 章 大野 友靖 塩入 孝之

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.3683-3685, 1984-09-25 (Released:2008-03-31)

参考文献数

12

被引用文献数

7 11

---

Condensation of carboxylic acids with tert-butyl hydroperoxide has been smoothly achieved by the use of diethyl phosphorocyanidate and triethylamine under mild reaction conditions, giving tert-butyl peroxycarboxylates in good yields.

著者

川口 健夫 実吉 峯郎

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.5, pp.1899-1901, 1988-05-25 (Released:2008-03-31)

参考文献数

15

---

Inhibition constants (Ki) of pyrimidine acyclonucleosides and several normal pyrimidine metabolites for the phosphorolytic degradation of 5-fluoro-2'-deoxyuridine (FUdR) in rat and beagle tissue homogenates (liver and small intestine) were measured. Acyclothymidine (AcycTdR) showed the lowest Ki value for all the homogenates. The Ki/Km values of AcycTdR and acyclouridine (AcycUdR) depended on the homogenates, and the values (Ki/Km) in the rat liver homogenate were higher than those in all other homogenates.

著者

星 昭夫 飯郷 正明 実吉 峯郎 榑谷 和男

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.7, pp.1535-1538, 1973-07-25 (Released:2008-03-31)

被引用文献数

4 4

---

Deamination of cytidine derivatives especially of cyclocytidine by mouse kidney cytidine deaminase was examined. Cyclocytidine was not deaminated at either pH6.5 or pH7.3 by the enzyme. Furthermore, cyclocytidine did not inhibit the deamination of aracytidine and ([I]/[S])0.5 value for cyclocytidine was over 100. As a result, cyclocytidine is found to be markedly active compound with resistance against cytidine deaminase.

著者

濱田 福三郎 杉原 太助 津山 伸吾 平山 八彦 金井 貞 西村 昌数 榑谷 和男 星 昭夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.23, no.3, pp.586-591, 1975-03-25 (Released:2008-03-31)

被引用文献数

1 1

---

Newly synthesized 5-3H-cyclocytidine was injected intravenously in rhesus monkeys having a high level of cytidine deaminase which inactivates aracytidine, an antitumor substance analogous to cyclocytidine, in human plasma and tissues. After rapid distribution as intact molecule in the liver, kidney, spleen, and other organs, 46.5% of the administered radioactivity was excreted via the renal pathway within 160min. Metabolite analysis of 5-3H-cyclocytidine in plasma, tissues, and urine of the monkeys revealed that extensive or rapid degradation of cyclocytidine did not occur, and confirmed the resistance of cyclocytidine against the deaminase activity and its stability in biological condition in vivo. Phosphorylated derivatives of cyclocytidine were also detected in the monkey liver after injection.

著者

HIRAKU ONISHI TAKEO KAWAGUCHI TSUNEJI NAGAI

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.3370-3374, 1987-08-25 (Released:2009-10-19)

参考文献数

22

被引用文献数

7 8

---

3'- (7-Carboxyheptanoyl) -5-fluoro-2'-deoxyuridine (C6-FUdR) was conjugated to decylenediamine-dextran T70 (T70-C10) or poly-L-lysine (PLL) by using 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC). Drug release patterns from the conjugates between C6-FUdR and T70-C10 (T70-C10-C6-FUdR) or PLL (PLL-C6-FUdR) by enzymatic and nonenzymatic processes were investigated at neutral and weakly acidic pHs. Under the nonenzymatic conditions, 5-fluoro-2'-deoxyuridine (FUdR) was released slowly only at neutral pH. This property is similar to that of C6-FUdR. Gradual drug release was observed enzymatically from T70-C10-C6-FUdR at both pHs, while PLL-C6-FUdR did not show enzymatic drug release. However, after the treatment of PLL-C6-FUdR with trypsin, FUdR was released enzymatically from the products; in this case, the release rate of FUdR was faster at neutral pH than at the weakly acidic pH. However, the release of FUdR by enzymatic processing was much slower from these conjugates than from C6-FUdR.

著者

川口 健夫 鈴木 嘉樹 南部 直樹 永井 恒司

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.7, pp.2956-2961, 1985-07-25 (Released:2008-03-31)

参考文献数

13

被引用文献数

6 8

---

Five acidic 3', 5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR) including 3-carboxypropionate, 4-carboxybutyrate, 5-carboxypentanoate, 6-carboxyhexanoate and 7-carboxyheptanoate were synthesized, and their susceptibility to porcine liver, rat liver homogenate, rat intestinal homogenate and rat plasma esterase preparations was studied. The susceptibility of the derivatives to porcine liver esterase preparation increased as the number of methylene groups in the ester promoiety increased in both acidic (pH 5.0) and neutral (pH 7.0) solutions. The derivatives showed about 100 times higher reactivity to the esterase at pH 5.0 than at pH 7.0. With the rat tissue homogenates and plasma preparations, the longer the ester chain the higher the susceptibility, except for 3', 5'-bis (3-carboxypropionyl) FUdR (I) with rat liver homogenate. Though the reactivity of I was the lowest with porcine liver esterase preparation and not measurable with rat intestinal homogenate and plasma, I showed the highest reactivity with the rat liver homogenate.

著者

川口 健夫 鈴木 嘉樹 中原 葉子 南部 直樹 永井 恒司

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.1, pp.301-307, 1985-01-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

13 16

---

The activity of porcine liver esterase towards diesters of 5-fluoro-2'-deoxyuridine with saturated aliphatic acids including acetic, propionic, butyric, hexanoic, octanoic, decanoic and dodecanoic acids was investigated. The susceptibility of the 3', 5'-diesters increased as the acyl chain was lengthened up to octanoyl, but further increase in the acyl chain length resulted in a sharp decrease in the susceptibility. The susceptibility of 3'-and 5'-monoesters increased as the chain was lengthened to decanoyl and slightly decreased on going to dodecanoyl. These results suggest that the higher antitumor activity of longer alkyl chain diesters of 5-fluoro-2'-deoxyuridine is partly due to their slow rates of hydrolysis by non-specific esterase.

著者

川口 健夫 斉藤 政彦 鈴木 嘉樹 南部 直樹 永井 恒司

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.4, pp.1652-1659, 1985-04-25 (Released:2008-03-31)

参考文献数

18

被引用文献数

21 24

---

The bioactivation characteristics of 3', 5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR) esterified with saturated aliphatic acids, including acetic, propionic, butyric, hexanoic, octanoic, decanoic, dodecanoic and trimethylacetic acids, were studied by using rat tissue homogenates and plasma. The susceptibility of the esters to hydrolysis by the biological media increased as the acyl promoiety was lengthened up to octanoyl. Further elongation resulted in decreasing susceptibility. Antitumor activity against L1210 of the esters with a longer chain or branched acyl group administered intraperitoneally and orally to tumor-bearing mice was also examined. Both the antitumor activity and the therapeutic index (ILSmax/ILS30) of the esters improved as the acyl promoiety was lengthened from octanoyl to dodecanoyl. These results suggested that the higher antitumor activities of longer alkyl chain diesters of FUdR are due to their slow rates of FUdR regeneration with esterases.

著者

実吉 峯郎 両角 正海 小玉 健次郎 町田 治彦 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.28, no.10, pp.2915-2923, 1980-10-25 (Released:2008-03-31)

参考文献数

24

被引用文献数

16 26

---

Enzymatic selective dephosphorylation of 1-β-D-arabinofuranosylcytosine 3', 5'-diphosphate (1) with nuclease-3'-nucleotidase P1 at 60° for 24 hr gave 1-β-D-arabinofuranosylcytosine 5'-phosphate (Ara CMP) (2) in good yield. The acylation of both N4- and the 2', 3'-hydroxyl groups of 2 followed by coupling with various alcohols and phenols in the presence of 2, 4, 6-triisopropylbenzenesulfonyl chloride and subsequent alkaline hydrolysis afforded the title compounds (4). The resulting 32 kinds of Ara CMP alkyl or aryl esters were examined to determine their biological activities, such as antiviral activity against herpes simplex type 1 in cultured human embryonic lung fibroblast cells, growth inhibitory activity against mouse leukemic L5178Y cells in culture and antileukemic activity against L-1210 in mice. Ara CMP esters were active in these assay systems.

著者

吉田 光二 星 昭夫 / 実吉 峯郎 MINEO SANEYOSHI

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.30, no.3, pp.1018-1023, 1982-03-25 (Released:2008-03-31)

参考文献数

23

被引用文献数

4 6

---

The mode of antiproliferative action of two 5-fluorocytosine nucleosides, 5-fluoro-cytidine (FCR) and 5-fluoro-2'-deoxycytidine (FCdR), was examined using mouse leukemia L5178Y cells in vitro. FCR and FCdR were markedly active against L5178Y cells, though the cells were deficient in cytidine deaminase activity. Both compounds increased the incorporation of 14C-labeled thymidine into the acid-insoluble fraction of L5178Y cells and decreased labeled deoxycytidine incorporation. In reversal studies, the antiproliferative effects of both compounds were almost abolished by simultaneous addition of thymidine or deoxyuridine. Deoxycytidine completely reversed the growth inhibition caused by FCdR, but not that caused by FCR. These results demonstrate that the cytotoxicity of both compounds is due to inhibition of thymidylate synthetase, presumably through formation of 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) after deamination by deoxycytidylate deaminase in the pyrimidine de novo pathway.

著者

吉田 光二 榑谷 和男 星 昭夫

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.2, pp.429-434, 1978-02-25 (Released:2008-03-31)

被引用文献数

2 3

---

5-Fluorouridine and 1-β-D-arabinofuranosylcytosine are active against various tumors as antimetabolites. Antitumor activity and mode of action of their nucleotides, 5-fluorouridine 5'-phosphate and 1-β-D-arabinofuranosylcytosine 5'-phosphate, were examined. 5-Fluorouridine 5'-phosphate was active similar to the nucleoside against L1210 leukemia, but the nucleotide showed higher therapeutic ratio than 5-fluorouracil and 5-fluorouridine. The mode of action of these nucleotides was examined by the incorporation of labeled precursors into acid-insoluble fraction of the cells for 30 min. Inhibition patterns of these nucleotides were the same as those of the nucleosides, but the potency of the nucleotides was very weak, and increased with time. Analysis showed that these nucleotides were dephosphorylated on the cell surface and the dephosphorylation was greater than that of phenolphthalein monophosphate. 5-Fluorouridine 5'-phosphate was considered to be a good candidate for an antitumor agent.

著者

/ 船越 和久 末宗 洋 大石 武 秋田 弘幸 酒井 浄 Kiyoshi Sakai

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.7, pp.3058-3060, 1986-07-25 (Released:2008-03-31)

参考文献数

9

被引用文献数

7 9

---

Microbial reduction of 7-methoxycarbonyl bicyclo[4. 3. 0]non-3-en-8-one ((±)-3) afforded the optically active (-)-3, which was efficiently converted by ring contraction using thallium (III) nitrate to the intermediate (11) used to synthesize carbacyclin (1).

著者

ZHUO-FENG XIE YUKINOBU ICHIKAWA HIROSHI SUEMUNE KIYOSHI SAKAI

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.5, pp.1812-1816, 1987-05-25 (Released:2009-10-19)

参考文献数

9

被引用文献数

4 7

---

The conversion of (+) -limonen-10-ol (7) into the key intermediate for the synthesis of carbacyclin (1), (+) - (1S, 2R, 3R, 5R) -3-acetoxy-2-methoxycarbony1-7-oxobicyclo [3.3.0] octane (2), is described. The cis-3, 4-disubstituted cyclopentanone prepared from 7 via a sequence of reactions involving Rh (I) -catalyzed cyclization could be converted to the 3-acetylbicyclo [3.3.0] oct-2-ene skeleton, which was subjected to 1, 4-addition reaction with CN-. The resulting cyano compound was transformed into the key intermediate 2 through appropriate modification of the substituents on the five-membered ring. This synthetic method provides a new route to carbacyclin.

著者

飯森 隆昌 村井 安 脇坂 康尋 大塚 晏央 大内 章吉 児玉 佳男 大石 武

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.4, pp.775-777, 1993-04-15 (Released:2008-03-31)

参考文献数

14

被引用文献数

2 8

---

Conformational restrictions of sangivamycin (1) could be achieved by the use of the gauche effect of the substitutents on the ribofranose moiety. The conformational deviations obtained by this method were found to nicely correlate with the inhibitory activity of PKC.

著者

池原 森男 伊村 純子

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.11, pp.3281-3285, 1981-11-25 (Released:2008-03-31)

参考文献数

10

被引用文献数

11 17

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The reaction of N2-isobutyryl-9-(2'-O-trifluoromethanesulfonyl-3', 5'-di-O-tetrahydrofuranyl-β-D-arabinofuranosyl) guanine with tetra-n-butylammonium fluoride or an appropriate metal halide in dimethylformamide aftorded N2-isobutyryl-3', 5'-di-O-tetrahydrofuranyl-2'-halogeno-2'-deoxyguanosines. The deprotection of these products led to 2'-halogeno-2'-deoxyguanosines. The ultraviolet absorption properties, 1H and 13C nuclear magnetic resonance spectral properties of the products were recorded.

著者

上杉 晴一 三木 弘子 池原 森男

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.8, pp.2199-2204, 1981-08-25 (Released:2008-03-31)

参考文献数

41

被引用文献数

3 7

---

^<13>C nuclear magnetic resonance spectra of various 2'-substituted 2'-deoxyadenosines are presented. The relative substituent chemical shifts of each sugar carbon are analyzed in terms of a substituent electronegativity parameter and compared with the data for substituted cyclohexanes. The relative substituent chemical shifts of C2' and C4' are controlled mainly by the inductive effect of the substituent. Those of C1' and C3' cannot be interpreted by inductive effect only. Some effect which is perturbed by the presence of a cis-substituent seems to be operating. A good linear correlation was observed between the substituent chemical shift of C2' and the N conformer population in the furanose puckering equilibrium.

著者

池原 森男 伊村 純子

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.4, pp.1034-1038, 1981-04-25 (Released:2008-03-31)

参考文献数

18

被引用文献数

15 16

---

2'-Deoxy-2'-fluoroguanosine (VII) was synthesized starting from 8, 2'-anhydro-8-oxy-9-β-D-arabinofuranosylguanine (8, 2'-O-cycloguanosine) (I). Compound I was protected at 2-NH2 with an isobutyryl group and at 3'- and 5'-OH with tetrahydrofuranyl groups. The protected compound III was derivatized to the arabino nucleoside V and thence converted to VII by treatment with trifluoromethanesulfonyl chloride and tetra-n-butylammonium fluoride. The resulting 2'-deoxy-2'-fluoroguanosine showed a 3'-endo favored conformation.

著者

/ 岩本 真承 青木 俊二 田中 直美 田嶋 清子 山原 條二 高石 喜久 吉田 雅昭 富松 利明 玉井 洋進 Yoshin TAMAI

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.39, no.2, pp.397-399, 1991-02-25 (Released:2008-03-31)

参考文献数

9

被引用文献数

40 73

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It has been reported that an acetone extract of ginger and its fractions have anti-5-HT (5-hydroxytryptamine; serotonin) effects. In the present study, guinea pig ileum, rat stomach fundus and rabbit aortic strips are used in order to determined the constituents of fraction 2 which are responsible for anti-5-HT effect and to examine their pharmacological properties.The analysis of fraction 2-3 indicated that galanolactone, a diterpenoid, is one of the active constituents. In guinea pig ileum, galanolactone inhibited contractile responses to 5-HT with a pIC50 value 4.93. pIC50 value of galanolactone against the response to 2-methyl-5-HT, a selective 5-HT3 agonist, in the presence of methysergide at 1×10-5M was 5.10. pIC50 values of ICS 205-930, a selective 5-HT3 antagonist, were 5.30 and 7.49, respectively. The concentration-response curve of 5-HT was shown as a biphasic curve and galanolactone caused a selective shift to the right of the second phase.In the same preparations, the pIC50 value of galanolactone and ICS 205-930 against the response to carbamylcholine (CCh) was 4.45 and 4.46.The inhibitory effect of galanolactone on the 5-HT response in the stomach fundus and aortic strips was less than that in the ileum.In addition, in the thoracic aorta precontracted with 50 mM K+, the relaxing effect of galanolactone was about 1/10 of that of papaverine.These results suggest that the anti-5-HT effect of galanolactone, a diterpenoid isolated from ginger, is related to antagonism of 5-HT3 receptors.

著者

末宗 洋 田中 正一 尾葉石 浩 酒井 浄

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.1, pp.15-21, 1988-01-25 (Released:2008-03-31)

参考文献数

9

被引用文献数

9 18

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Synthesis of prostaglandin A2 (PGA2) by means of a route involving enzymatic reactions is described. Enantioselective reduction and hydrolysis of trans-3, 4-bis(methoxycarbonyl)cyclopentanone (1) were examined using yeasts or enzymes, and it was found that (+)- and (-)-1 are easily obtained by an enzymatic procedure. Compound (+)-1 was converted to the Corey intermediate for PGA2 via the regioselective hydrolysis of the (+)-diacetate (8) with porcine pancreatic lipase. This synthesis based on the enzymatic approach was proved to be useful for the synthesis of both PGA and PGE from (-)-1.