Comparison of Inhibitory Activities of Stereo-Isomers of Cyclic Phosphatidic Acid (cPA) on Autotaxin

• Nozaki Emi

  Graduate School of Humanities and Sciences, Department of Life Sciences, Ochanomizu University

• Gotoh Mari

  Graduate School of Humanities and Sciences, Department of Life Sciences, Ochanomizu University

• Hanazawa Shuwa

  Graduate School of Humanities and Sciences, Department of Life Sciences, Ochanomizu University Faculty of Pharmaceutical Sciences, Tokyo University of Science

• Mori Hirotoshi

  Division of Advanced Sciences, Ocha-dai Academic Production, Ochanomizu University

• Kobayashi Susumu

  Faculty of Pharmaceutical Sciences, Tokyo University of Science

• Murakami-Murofushi Kimiko

  Graduate School of Humanities and Sciences, Department of Life Sciences, Ochanomizu University

抄録

Cyclic phosphatidic acid (cPA) has a similar structure to that of lysophosphatidic acid (LPA), but possesses distinct biological functions. For example, cPA suppresses cancer cell invasion and metastasis through the inhibition of autotaxin (ATX) and transient activation of low molecular weight GTPase, RhoA. We designed and chemically synthesized several metabolically stabilized derivatives of cPA, and revealed that 2-carba-cPA was the most potent inhibitor of cancer cell invasion and metastasis. We have developed a novel method of 2ccPA enantiomeric synthesis, and here we examined the effects of natural (R)-cPA, both enantiopure 2ccPA, and (S)-3ccPA (corresponding to the configuration of (R)-2ccPA) on ATX. We also predicted the effects of (R)-cPA, (R)-2ccPA and (S)-3ccPA on ATX activity by combined quantum mechanics and molecular mechanics (QM/MM) computational methods. By these methods, we demonstrated that 2ccPA was the most potent inhibitor on ATX, and the chirality of 2ccPA was not involved in ATX inhibition. These results suggest that racemic-2ccPA may be utilized as an effective compound for cancer therapeutics.

収録刊行物

• ＣＹＴＯＬＯＧＩＡ

  ＣＹＴＯＬＯＧＩＡ 76 (1), 73-80, 2011

  公益財団法人 日本メンデル協会

キーワード

• Cyclic phosphatidic acid
• 2-Carba-cyclic phosphatidic acid
• 3-Carba-cyclic phosphatidic acid
• Autotaxin
• Cancer cell invasion
• Stereoselectivity

詳細情報

• CRID: 1390001204108946816
• NII論文ID: 130004448106
• DOI: 10.1508/cytologia.76.73
• ISSN: 13487019
• ISSN: 00114545
• Web Site: http://www.jstage.jst.go.jp/article/cytologia/76/1/76_1_73/_pdf
• 本文言語コード: en
• データソース種別:
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  • Crossref
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可