(9S)-9-dihydro-9,11-O-isopropylidene-3-O-((7-(N-methylcarbamoylguanidino)heptyl)carbamoyl)-5-O-propargylerythronolide A

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: (9S)-9-dihydro-9,11-O-isopropylidene-3-O-((7-(N-methylcarbamoylguanidino)heptyl)carbamoyl)-5-O-propargylerythronolide A
• 英文别名: (1r,2r,3r,6r,7s,8s,9r,10r,12r,13s,17s)-3-Ethyl-2,10-Dihydroxy-2,6,8,10,12,15,15,17-Octamethyl-5-Oxo-9-(Prop-2-Yn-1-Yloxy)-4,14,16-Trioxabicyclo[11.3.1]heptadec-7-Yl {7-[n'-(Methylcarbamoyl)carbamimidamido]heptyl}carbamate；[(1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,17S)-3-ethyl-2,10-dihydroxy-2,6,8,10,12,15,15,17-octamethyl-5-oxo-9-prop-2-ynoxy-4,14,16-trioxabicyclo[11.3.1]heptadecan-7-yl] N-[7-[[amino-(methylcarbamoylamino)methylidene]amino]heptyl]carbamate
• 化学式: C₃₈H₆₇N₅O₁₀
• 分子量: 753.977
• InChiKey: AQAYUMFDPSWMFV-BLJMIVIQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  53
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  212
• 氢给体数：
  6
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (9S)-9-dihydro-9,11-O-isopropylideneerythronolide A 在 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 6.33h， 生成 (9S)-9-dihydro-9,11-O-isopropylidene-3-O-((7-(N-methylcarbamoylguanidino)heptyl)carbamoyl)-5-O-propargylerythronolide A
  参考文献：
  名称：

  Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase

  摘要：

  Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits similar to 200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.

  DOI：

  10.1021/acs.jmedchem.5b00175

文献信息

• Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase
  作者：Akihiro Sugawara、Nobuo Maita、Hiroaki Gouda、Tsuyoshi Yamamoto、Tomoyasu Hirose、Saori Kimura、Yoshifumi Saito、Hayato Nakano、Takako Kasai、Hirofumi Nakano、Kazuro Shiomi、Shuichi Hirono、Takeshi Watanabe、Hisaaki Taniguchi、Satoshi O̅mura、Toshiaki Sunazuka

  DOI：10.1021/acs.jmedchem.5b00175

  日期：2015.6.25

  Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits similar to 200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.