(15S,18R)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-3,16-dione | 111359-05-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (15S,18R)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-3,16-dione
• CAS: 111359-05-8
• 化学式: C₂₅H₁₇N₃O₃
• 分子量: 407.428
• InChiKey: JDHOAXUYMDBHEM-CJAUYULYSA-N

物化性质

• 沸点：
  677.0±55.0 °C(Predicted)
• 密度：
  1.70±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  31
• 可旋转键数：
  0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  65.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (15S,18R)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-3,16-dione 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 氢氧化钾 、 甲酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 甲苯 为溶剂， 反应 29.75h， 生成 (+)-抗生素K252A
  参考文献：
  名称：

  Stereocontrolled Total Synthesis of (+)-K252a

  摘要：

  DOI：

  10.1021/ja990909l
• 作为产物：
  描述：

  来他替尼 在 高碘酸 作用下， 以 四氢呋喃 为溶剂， 以83%的产率得到(15S,18R)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-3,16-dione
  参考文献：
  名称：

  Synthesis, Modeling, and In Vitro Activity of (3‘S)-epi-K-252a Analogues. Elucidating the Stereochemical Requirements of the 3‘-Sugar Alcohol on trkA Tyrosine Kinase Activity

  摘要：

  Utilizing our recently published semisynthetic approach to the (3'S)-K-252a diastereomer, we report the first synthesis of the (3'R)-10 diastereomer and a set of related epimers, with the goal of defining the stereochemical role of the 3'-sugar hydroxyl group on trkA tyrosine kinase activity and selectivity. (3'R)-10 displayed potent trkA inhibitory activity with an IC50 value of 4 nM. The corresponding deshydroxy epimer (3'S)-14 was 7-fold more potent than its 3'R counterpart (natural stereochemistry) with a trkA IC50 value of 3 nM and demonstrated > 280-fold selectivity over PKC (IC50 = 850 nM). In cells, (3'S)-14 displayed potent inhibition of trkA autophosphorylation with an IC50 < 10 nM. Molecular modeling studies revealed that the X-OH, due to the inverted geometry, forms significant H-bonding interactions with Glu27 and Arg195, an interaction that is not attainable with the natural isomers.

  DOI：

  10.1021/jm040178m

文献信息

• Synthesis and kinase inhibitory activity of 3′-(S)-epi-K-252a
  作者：Diane E. Gingrich、Robert L. Hudkins

  DOI：10.1016/s0960-894x(02)00638-8

  日期：2002.10

  The 3'-epi diastereomer of K-252a was synthesized with the goal of evaluating the stereochemical requirements of the 3'-sugar alcohol on kinase inhibitory activity. Inverting the 3'-alcohol resulted in a 20 nM inhibitor of VEGFR2 and a 1 nM inhibitor of TrkA tyrosine kinase. (C) 2002 Elsevier Science Ltd. All rights reserved.
• DEUTERIUM-ENRICHED LESTAURTINIB
  申请人：Czarnik Anthony W.

  公开号：US20080299215A1

  公开（公告）日：2008-12-04

  The present application describes deuterium-enriched lestaurtinib, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.
• Synthesis, Modeling, and In Vitro Activity of (3‘<i>S</i>)-<i>e</i><i>pi</i>-K-252a Analogues. Elucidating the Stereochemical Requirements of the 3‘-Sugar Alcohol on trkA Tyrosine Kinase Activity
  作者：Diane E. Gingrich、Shi X. Yang、George W. Gessner、Thelma S. Angeles、Robert L. Hudkins

  DOI：10.1021/jm040178m

  日期：2005.6.1

  Utilizing our recently published semisynthetic approach to the (3'S)-K-252a diastereomer, we report the first synthesis of the (3'R)-10 diastereomer and a set of related epimers, with the goal of defining the stereochemical role of the 3'-sugar hydroxyl group on trkA tyrosine kinase activity and selectivity. (3'R)-10 displayed potent trkA inhibitory activity with an IC50 value of 4 nM. The corresponding deshydroxy epimer (3'S)-14 was 7-fold more potent than its 3'R counterpart (natural stereochemistry) with a trkA IC50 value of 3 nM and demonstrated > 280-fold selectivity over PKC (IC50 = 850 nM). In cells, (3'S)-14 displayed potent inhibition of trkA autophosphorylation with an IC50 < 10 nM. Molecular modeling studies revealed that the X-OH, due to the inverted geometry, forms significant H-bonding interactions with Glu27 and Arg195, an interaction that is not attainable with the natural isomers.
• Stereocontrolled Total Synthesis of (+)-K252a
  作者：Yoshihisa Kobayashi、Teppei Fujimoto、Tohru Fukuyama

  DOI：10.1021/ja990909l

  日期：1999.7.1