(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one | 97161-97-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one
• 英文别名: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b-11a-triazadibenzo[a,g]-cycloocta[c,d,e]-trinden-1-one；(8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cyclo-octa[c,d,e]trinden-1-one；(3'S)-epi-K-252a；3'(S)-epi-K-252a；K-252a；K252a；K-252A(Epi)；methyl (15S,16S,18R)-16-hydroxy-15-methyl-3-oxo-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-carboxylate
• CAS: 97161-97-2
• 化学式: C₂₇H₂₁N₃O₅
• 分子量: 467.481
• InChiKey: KOZFSFOOLUUIGY-BLIZRMSTSA-N

物化性质

• 熔点：
  262-2630C
• 溶解度：
  DMF：1 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  35
• 可旋转键数：
  2
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  94.7
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• 海关编码：
  29349990

反应信息

• 作为反应物：
  描述：

  (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one 、 N-溴代丁二酰亚胺(NBS) 生成 methyl (15S,16S,18R)-12,21-dibromo-16-hydroxy-15-methyl-3-oxo-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate
  参考文献：
  名称：

  KOYAMA, MASAO;XATISU, MITSUGU;IVATA, MITIAKI;KODZIMA, MITIO;KAI, FUMIO;SE+

  摘要：

  DOI：
• 作为产物：
  描述：

  来他替尼 在 盐酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one
  参考文献：
  名称：

  Synthesis and kinase inhibitory activity of 3′-(S)-epi-K-252a

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(02)00638-8

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.
• KOYAMA, MASAO;XATISU, MITSUGU;IVATA, MITIAKI;KODZIMA, MITIO;KAI, FUMIO;SE+
  作者：KOYAMA, MASAO、XATISU, MITSUGU、IVATA, MITIAKI、KODZIMA, MITIO、KAI, FUMIO、SE+

  DOI：——

  日期：——
• 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.