Synthesis and Antitumor Activity of New Alkylphospholipids Containing Modifications of the Phosphocholine Moiety

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概要

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• New antitumor alkylglycerophospholipids, in which primarily the phosphocholine moiety of the platelet activating factor (PAF) molecule was modified, were synthesized from 1-alkyl-2-substituted glycerols by introducing polar head phosphoryl groups having methylene bridges of various lengths (from 2 to 14 carbons). They were tested for PAF agonistic activity and antitumor properties. In a series of 1-octadecyl-2-acetoacetylglycerophospholipids (1a-f), an increase in the length of the methylene bridge separating the phosphate and trimethylammonio group in the polar head side chain at position 3 of the glycerol backbone resulted in a progressive decrease in PAF agonistic activity and a characteristic change in antitumor activity against human promyelocytic leukemia cells (HL-60). Maximal potency was obtained with the compound having a decamethylene bridge (1e, IC_<50> value=1.5 μg/ml). Thus, alkylphospholipids possessing a decanmethylene bridge and a variety of substituents at position 2 (1g-n) were synthesized. They showed potent inhibitory activity with IC_<50> values ranging from 0.4 to 1.9 μg/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (1a-n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), 1-octadecyl-2-acetoacetyl-3-glyceryl ω-trimethylammoniodecyl phosphate (1e) showed the most potent life-prolonging effect. The structure-activity relationships are discussed.

• 社団法人日本薬学会の論文
• 1989-05-25

著者

• 水野 克利

  Chemistry Research Laboratories Research and Development Division, Takeda Chemical Industries, Ltd.

• 穂積 本男

  Department Of Chemotherapy Saitama Cancer Center Research Institute

• 穂積 本男

  Department Of Chemotherapy Saitama Cancer Center Research Institure

• 寺下 善一

  武田薬品工業(株)生物研究所

• 山本 弘昭

  Pharmaceutical Research Division Pharmaceutical Research Laboratories Iii Takeda Chemical Industires

• 工藤 一郎

  Faculty of Pharmaceutical Sciences, The University of Tokyo

• 井上 圭三

  Faculty of Pharmaceutical Sciences, The University of Tokyo

• 鵜川 清

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 今宮 栄光

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 山本 弘昭

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 水野 克利

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 田坂 昭弘

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 寺下 善一

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 奥谷 哲也

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 野村 容朗

  Central Research Division, Takeda Chemical Ind., Ltd.,

• 粕壁 隆

  Department of Chemotherapy, Saitama Cancer Center Research Institute

• 水野 克利

  Chemistry Research Laboratories Research And Development Division Takeda Chemical Industries Ltd.

• 田坂 昭弘

  Pharmaceutical Research Laboratories Iii Pharmaceutical Research Division Takeda Chemical Industries

• 野村 容朗

  Research and Development Division, Eisai Company, Ltd.,

• 今宮 栄光

  Resarch & Development Division Takeda Chemical Industries Ltd.

• 奥谷 哲也

  Resarch & Development Division Takeda Chemical Industries Ltd.

• 奥谷 哲也

  Central Research Division Takeda Chemical Industries Ltd.

• 野村 容朗

  Research And Development Division Eisai Company Ltd.

• 鵜川 清

  Resarch & Development Division Takeda Chemical Industries Ltd.

• Nomura Hiroaki

  Research And Development Division Eisai Company Ltd.

• 田坂 昭弘

  Central Research Division Takeda Chemical Ind. Ltd.

• 粕壁 隆

  Department Of Chemotherapy Saitama Cancer Center Research Institute

• Yamamoto Hiroaki

  Pharmaceutical Research Division Pharmaceutical Research Laboratories Iii Takeda Chemical Industries

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