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

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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

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

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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

松下 仁 小室 昌仁 前田 利松 南 慶典 佐川 久美子

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.42, no.Supplement2, pp.198-205, 1994-10-24 (Released:2011-08-04)

参考文献数

9

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Tazobactam/piperacillin (TAZ/PIPC) の代謝物の検索をラジオ-HPLCを用いて, また活性代謝物の検索をTLC-バイオオートグラフィーを用いて検討した。次にtazobactam (TAZ) の代謝物M-1の生成臓器について, 血漿, 臓器ホモジネートを用いたin vitro試験により検討し, 次の結果を得た。1. ラットに14C-TAZ/PIPCあるいはTAZ/14C-PIPCを静脈内投与して, 血漿, 尿および胆汁中代謝物を検索し, 定量した。TAZの代謝物として, β-ラクタム環が開裂・分解した構造を有するM-1を同定した。Piperacillin (PIPC) は主として未変化体として検出され, 主要代謝物は存在しなかった。ラットの尿中にはTAZ未変化体が約70%, TAZの代謝物M-1が約17%, PIPC未変化体が約25%排泄された。胆汁中にはTAZが約2%, M-1が約1%, PIPCが約60%排泄された。2. ラット, イヌおよびサルにTAZ/PIPC50mg/kgを投与して, 血漿および尿のバイオオートグラムを作製し, 活性代謝物を検索した。その結果, TAZ, PIPCともに, 標準品と同位置に1スポットのみ検出され, 活性代謝物は存在しなかった。3. マウスの肺, 肝, 腎, 小腸の25%ホモジネートおよび血漿中の安定性について検討した。マウスでは血漿, 腎, 小腸でM-1が生成した。

著者

吉田 健一郎 東 龍太郎 佐伯 真由子 南 慶典 大谷 敏夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 35 (ISSN:24331856)

巻号頁・発行日

pp.250-257, 1993-09-10 (Released:2017-08-18)

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Antibiotic C-1027, a novel antitumor chromoprotein isolated from the broth filtrate of Streptomyces globisporus C-1027, shows extremely potent cytotoxicity against KB carcinoma cells (IC_<50> 0.1ng/ml) in vitro and antitumor activity toward tumor-bearing mice in vivo. These activities are correlated with the ability of the antibiotic to cause DNA double-strand scission. The antibiotic consists of an apoprotein and a labile chromophore (C-1027-Chr) that is responsible for the biological activity of C-1027. The chromophore is readily separated from its apo-protein by extraction, but the exceeding instability in the protein-free state hampered the structure elucidation. The similar situation has been also observed in the other chromoprotein antibiotics of this family such as neocarzinostatin (NCS), macromomycin, auromomycin (AUR), actinoxanthin and kedarcidin. Among them, NCS is the only one whose chromophore structure has been elucidated, and very recently, the structural novelty of kedarcidin chromophore has been disclosed by the Bristol-Myers Squibb group. We have characterized an inactive but more stable reaction product (2) of C-1027-Chr, which was prepared by treatment of C-1027-Chr in ethanol. It possesses a macrocyclic structure together with oxazolinate and aminosugar moieties as side chains. Its benzodihydropentalene core structure suggested to us the presence of an enediyne in the native C-1027-Chr. We disclose herein the novel structure of C-1027-Chr (1) and the cycloaromatization mechanism leading to product (2), which would explain its extreme potency in terms of cytotoxicity and ability to cause DNA double-strand scission.

著者

吉田 健一郎 東 龍太郎 佐伯 真由子 南 慶典 大谷 敏夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.35, pp.250-257, 1993

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Antibiotic C-1027, a novel antitumor chromoprotein isolated from the broth filtrate of Streptomyces globisporus C-1027, shows extremely potent cytotoxicity against KB carcinoma cells (IC_<50> 0.1ng/ml) in vitro and antitumor activity toward tumor-bearing mice in vivo. These activities are correlated with the ability of the antibiotic to cause DNA double-strand scission. The antibiotic consists of an apoprotein and a labile chromophore (C-1027-Chr) that is responsible for the biological activity of C-1027. The chromophore is readily separated from its apo-protein by extraction, but the exceeding instability in the protein-free state hampered the structure elucidation. The similar situation has been also observed in the other chromoprotein antibiotics of this family such as neocarzinostatin (NCS), macromomycin, auromomycin (AUR), actinoxanthin and kedarcidin. Among them, NCS is the only one whose chromophore structure has been elucidated, and very recently, the structural novelty of kedarcidin chromophore has been disclosed by the Bristol-Myers Squibb group. We have characterized an inactive but more stable reaction product (2) of C-1027-Chr, which was prepared by treatment of C-1027-Chr in ethanol. It possesses a macrocyclic structure together with oxazolinate and aminosugar moieties as side chains. Its benzodihydropentalene core structure suggested to us the presence of an enediyne in the native C-1027-Chr. We disclose herein the novel structure of C-1027-Chr (1) and the cycloaromatization mechanism leading to product (2), which would explain its extreme potency in terms of cytotoxicity and ability to cause DNA double-strand scission.