ロイコマイシン類を出発物質としたラクトンの化学変換と新規アザライドの創出 Chemical Transformation of Lactone Starting from 16-Membered Macrolides, Leucomycins, and Generation of Novel Azalides

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For the purpose of generation of a new macrolide antibiotic which is effective against constitutive <i>erm</i>-resistant <i>Streptococcus pneumoniae</i>, a variety of novel 11-azalides were designed and synthesized starting from 16-membered macrolides, leucomycins. One step macrocyclization by a linear dialdehyde and a primary amine <i>via</i> reductive amination firstly gave 15-membered 11-azalide, and optimized 11-<i>N</i>-arylalkyl-azalide was effective against inducible <i>erm</i>-resistant <i>S. pneumoniae</i>. Then, 14-membered to 16-membered 11-azalides or 11-azalactams were systematically prepared in application of a formylcarboxylic acid, and biologically evaluated. As a result, 16-membered 11-azalide was chosen as a lead compound for further medicinal chemistry. Finally 16-membered 15-β-substituted-11-azalide was generated as a clinical candidate through determination of the position of an arylalkyl group to be inserted and its stereochemistry, optimization of the arylalkyl group and the C-3 position, and exploration of a neutral sugar moiety for enhancement of stability against metabolism. This molecule exhibited strong activities against not only constitutive <i>erm</i>-resistant <i>S. pneumoniae</i> but resistant <i>S. pneumoniae</i> with <i>mef</i> gene and resistant <i>Streptococcus pyogenes</i>.

収録刊行物

  • 有機合成化学協会誌

    有機合成化学協会誌 69(12), 1339-1351, 2011-12-01

    社団法人 有機合成化学協会

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  • NII論文ID(NAID)
    10030480355
  • NII書誌ID(NCID)
    AN0024521X
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    JPN
  • 資料種別
    ART
  • ISSN
    00379980
  • NDL 記事登録ID
    023364610
  • NDL 請求記号
    Z17-256
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    CJP書誌  NDL  J-STAGE 
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