Synthesis and Antitumor Activity of New Amphiphilic Alkylglycerolipids Substituted with a Polar Head Group, 2-(2-Trimethylammonioethoxy)ethyl or a Congeneric Oligo(ethyleneoxy)ethyl Group

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• A new series of amphiphilic 1-octadecyl glycerolipids (eleven compounds, 1a-k) were designed and synthesized, in which the 3-phosphocholine portion of platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) was replaced by the 2-(2-trimethylammonioethoxy)ethyl group and congeneric groups having oligo(ethyleneoxy)ethyl bridges of various lengths at position 3,together with modification at position 2 (lower alkyl, acetonyl, acetoacetyl, carboxymethyl and pyrimidin-2-yl groups). These ether lipids, characterized by a nonphosphorus lysoglycerolipid structure, showed potent antitumor activity in vitro (human promyelocytic leukemia cells, HL-60,and human epidermoid carcinoma cells, KB) and in vivo (mouse sarcoma S180 and mouse mammary carcinoma MM46). Maximal in vitro potency was obtained with 1-O-octadecyl-2-O-(2-pyrimidinyl)-3-O-[2-(2-trimethylammonioethoxy)ethyl]glycerol (1g; IC_<50> values for both HL-60 and KB were 0.32 μg/ml, indicating a higher activity than alkyl-lysophospholipid, ET18-OMe). Several appropriately 2-substituted 1-octadecylglycerolipids with the 3-[2-(2-trimethylammonioethoxy)ethyl]group (e.g., methyl, 1b; butyl, 1f; 2,2,2-trifluoroethyl, 1g; and acetonyl, 1k) showed a potent life-span-prolonging effect on mice with ascites sarcoma S180 and on those with mammary carcinoma MM46,when administered intraperitoneally at 16.5 and 12.5 mg/kg/d, respectively. Compounds 1b and 1k showed definite tumor growth inhibition against solid sarcoma S180 in mice, whether given p.o. or i.v. at 16.5 gm/kg/d. Studies on the structure-activity relationships indicate that the metabolic stability to phospholipase C or related enzymes is at least partly responsible for the potent antitumor activity of this series of ether lipids.

• 社団法人日本薬学会の論文
• 1989-12-25

著者

• 青野 哲也

  Resarch & 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

• 本間 良夫

  Department of Chemotherapy, Saitama Cancer Center Research Institure

• 山本 弘昭

  Pharmaceutical Research Division Pharmaceutical Research Laboratories Iii Takeda Chemical Industires

• 鵜川 清

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 今宮 栄光

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 山本 弘昭

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 香西 義雄

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 奥谷 哲也

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 野村 容朗

  Resarch & Development Division, Takeda Chemical Industries, Ltd.,

• 工藤 一郎

  Faculty of Pharmaceutical Sciences, The University of Tokyo

• 井上 圭三

  Faculty of Pharmaceutical Sciences, The University of Tokyo

• 香西 義雄

  Pharmaceutical Research Division Takeda Chemical Industries Ltd.

• 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.

• 野村 容朗

  Research And Development Division Eisai Company Ltd.

• 鵜川 清

  Resarch & Development Division Takeda Chemical Industries Ltd.

• 本間 良夫

  Department Of Chemotherapy Saitama Cancer Center Research Institure

• Nomura Hiroaki

  Research And Development Division Eisai Company Ltd.

• Yamamoto Hiroaki

  Pharmaceutical Research Division Pharmaceutical Research Laboratories Iii Takeda Chemical Industries

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