新規抗菌剤開発を指向したMraY阻害天然物ムライマイシン類の合成研究

  • 谷野 哲也
    北海道大学大学院生命科学院
  • 市川 聡
    北海道大学大学院生命科学院 北海道大学大学院薬学研究院
  • 魚谷 幸一
    塩野義製薬株式会社中央研究所
  • 大山 洋
    塩野義製薬株式会社シオノギ創薬イノベーションセンター
  • 松田 彰
    北海道大学大学院生命科学院 北海道大学大学院薬学研究院

書誌事項

タイトル別名
  • Comprehensive Synthetic Study of Muraymycins toward the Development of Novel Antibacterial Agents
  • シンキ コウキンザイ カイハツ オ シコウ シタ MraY ソガイ テンネンブツ ムライマイシンルイ ノ ゴウセイ ケンキュウ

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説明

  This review describes the synthesis and structure-activity relationship (SAR) study of muraymycins (MRYs), which are potent antibacterial nucleoside antibiotics. The key elements of our synthetic approach include the preparation of L-epi-capreomycidine via a C-H amination reaction and a convergent assemblage to construct of the framework of MRYs using Ugi four component reaction. With this approach the first total synthesis of MRY D2 and its epimer, epi-MRY D2, which does not have lipophilic substituents, has been accomplished. The fact that MRY D2 and it's epimer did not show any antibacterial activity indicated the lipophilic substituents of MRYs plays an important role in membrane-permeability. Hence, MRY analogues with lipophilic substituents were designed and synthesized simply by altering the aldehyde component in Ugi four-component assemblage. The MRY analogues with lipophilic substituents exhibited improved antibacterial activity against anti drug-resistant bacteria. It was also suggested that the accessory urea-dipeptide motif might contribute to MraY inhibitory and antibacterial activity. Our synthetic approach would effectively provide a variety of MRY analogues and resultant SAR information brings us directions to create further MRY analogues.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 131 (3), 335-346, 2011

    公益社団法人 日本薬学会

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