(15S,16S,18R)-15-methylspiro[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-16,2'-oxirane]-3-one | 229983-06-6

• 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,16S,18R)-15-methylspiro[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-16,2'-oxirane]-3-one
• CAS: 229983-06-6
• 化学式: C₂₆H₁₉N₃O₃
• 分子量: 421.455
• InChiKey: NCTSFCFTKAEUMY-LROUJFHJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  32
• 可旋转键数：
  0
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  60.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (15S,16S,18R)-15-methylspiro[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-16,2'-oxirane]-3-one 在 三乙基硼氢化锂 作用下， 以 四氢呋喃 为溶剂， 以83%的产率得到(15S,16R,18R)-16-hydroxy-15,16-dimethyl-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-nonaen-3-one
  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
• 作为产物：
  描述：

  来他替尼 在 4-二甲氨基吡啶 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (15S,16S,18R)-15-methylspiro[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-16,2'-oxirane]-3-one
  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, 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.