5'-<4-<<<4-(trans-2-nitroethenyl)phenyl>oxy>sulfonyl>benzoyl>adenosine | 134360-38-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 5'-<4-<<<4-(trans-2-nitroethenyl)phenyl>oxy>sulfonyl>benzoyl>adenosine
• 英文别名: 5'-[4-({[4-(trans-2-nitroethenyl)phenyl]oxy}sulfonyl)benzoyl]adenosine；[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl 4-[4-[(E)-2-nitroethenyl]phenoxy]sulfonylbenzoate
• CAS: 134360-38-6
• 化学式: C₂₅H₂₂N₆O₁₀S
• 分子量: 598.55
• InChiKey: UHYWUEAMUOPMRO-YSKCLZGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  243
• 氢给体数：
  3
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  反-4-羟基-β-硝基苯乙烯 在 sodium hydroxide 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 5'-<4-<<<4-(trans-2-nitroethenyl)phenyl>oxy>sulfonyl>benzoyl>adenosine
  参考文献：
  名称：

  Sulfonylbenzoyl-nitrostyrenes: Potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase

  摘要：

  The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less-than-or-equal-to 1-mu-M. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.

  DOI：

  10.1021/jm00112a003

文献信息

• TRAXLER, PETER M.;WACKER, OSKAR;BACH, HA L.;GEISSLER, JOHANNA F.;KUMP, WI+, J. MED. CHEM., 34,(1991) N, C. 2328-2337
  作者：TRAXLER, PETER M.、WACKER, OSKAR、BACH, HA L.、GEISSLER, JOHANNA F.、KUMP, WI+

  DOI：——

  日期：——
• Sulfonylbenzoyl-nitrostyrenes: Potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase
  作者：Peter M. Traxler、Oskar Wacker、Ha L. Bach、Johanna F. Geissler、Wilhelm Kump、Thomas Meyer、Urs Regenass、Johannes L. Roesel、Nicholas Lydon

  DOI：10.1021/jm00112a003

  日期：1991.8

  The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less-than-or-equal-to 1-mu-M. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.