A New Class of Nitrosoureas. II. Synthesis and Antitumor Activity of 1-(2-Chloroethyl)-3,3-disubstituted-1-nitrosoureas having a Glucopyranosyl, Mannopyranosyl or Galactopyranosyl Moiety
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概要
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Many kinds of 1-(2-chloroethyl)-3-substituted-3-β-D-glycopyranosyl-1-nitrosoureas (V) were synthesized and tested for antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma. The reaction of aldohexoses such as D-glucose, D-mannose, and D-galactose with primary amines followed by treatment with 2-chloroethyl isocyanate usually gave a mixture of structural isomers of glycosylureas (III'). Complete isomerization into thermodynamically stable β-D-glycopyranosylureas (III) was observed when the mixture of isomers was dissolved in formic acid. Glycopyranosylureas (III) were nitrosated with 5 equivalents of dinitrogen tetroxide followed by treatment with methanol to give the corresponding nitrosoureas (V) in good yields. Many of the nitrosoureas (V) were remarkably active against both leukemia L1210 and Ehrlich ascites carcinoma and showed greater therapeutic ratios than those of the positive controls, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 3 [(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)-1-nitrosourea. In particular, some of the galactopyranosylnitrosoureas showed excellent antitumor activities and sixtyday survivors against leukemia L1210 were observed at dose levels of 25,50 and 100 mg/kg of the compounds. These nitrosoureas (V) appear to be activated nonenzymatically by attack of the hydroxyl group of the sugar moiety on the carbonyl group to give the cyclic carbamate (VI) without generation of the isocyanate (XI).
- 社団法人日本薬学会の論文
- 1981-11-25
著者
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宮崎 道彦
Organic Chemistry Research Laboratory Tanabe Seiyaku Co. Ltd.
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宮崎 道彦
Research Laboratories Tanabe Seiyaku Co. Ltd.
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川森 政敏
Organic Chemistry Research Laboratory
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森川 民雄
Organic Chemistry Research Laboratory
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辻原 健二
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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大関 正勝
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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森川 民雄
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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多賀 尚正
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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川森 政敏
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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新井 淑久
Research Laboratories, Tanabe Seiyaku Co., Ltd.
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新井 淑久
Research Laboratories Tanabe Seiyaku Co. Ltd.
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多賀 尚正
Research Laboratories Tanabe Seiyaku Co. Ltd.
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大関 正勝
Research Laboratories Tanabe Seiyaku Co. Ltd.
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辻原 健二
Lead Optimization Research Laboratory Tanabe Seiyaku Co. Ltd.
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辻原 健二
Research Laboratories Tanabe Seiyaku Co. Ltd.
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