(2S,3R,4R,5R,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-4-hydroxy-6-propyltetrahydro-2H-pyran-3,5-diyl diacetate | 1266714-89-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: (2S,3R,4R,5R,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-4-hydroxy-6-propyltetrahydro-2H-pyran-3,5-diyl diacetate
• 英文别名: [(2S,3R,4R,5R,6S)-5-acetyloxy-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-4-hydroxy-2-propyloxan-3-yl] acetate
• CAS: 1266714-89-9
• 化学式: C₂₇H₂₈O₁₂
• 分子量: 544.512
• InChiKey: KJNVQQRKZXSWGI-WGXSRGGHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  178
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  5,7-二-(苄氧基)-2-(4-(苄氧基)苯基)-3-羟基-4H-苯并吡喃-4-酮 在 原乙酸三甲酯 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 sodium tetrahydroborate 、 四氧化锇 、 cerium(III) chloride 、 palladium 10% on activated carbon 、 氢气 、 对甲苯磺酸 、 N-甲基吗啉氧化物 、 三苯基膦 、 叔丁醇 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 丙酮 、 乙腈 为溶剂， -90.0~20.0 ℃ 、101.33 kPa 条件下， 反应 21.0h， 生成 (2S,3R,4R,5R,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-4-hydroxy-6-propyltetrahydro-2H-pyran-3,5-diyl diacetate
  参考文献：
  名称：

  Improving the Affinity of SL0101 for RSK Using Structure-Based Design

  摘要：

  Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product SL0101 (kaempferol 3-O-(3 '',4 ''-di-O-acetyl-alpha-L-rhamnopyranoside)) has been shown to be an RSK selective inhibitor. However, the K-i for SL0101 is 1 mu M with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5 ''-n-propyl group on the rhamnose that has >40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5 ''-n-propyl analogue to inhibit MCF-7 proliferation was only 2-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5 ''-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.

  DOI：

  10.1021/ml300298v

文献信息

• Improving the Affinity of SL0101 for RSK Using Structure-Based Design
  作者：Roman M. Mrozowski、Rajender Vemula、Bulan Wu、Qi Zhang、Benjamin R. Schroeder、Michael K. Hilinski、David E. Clark、Sidney M. Hecht、George A. O’Doherty、Deborah A. Lannigan

  DOI：10.1021/ml300298v

  日期：2013.2.14

  Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product SL0101 (kaempferol 3-O-(3 '',4 ''-di-O-acetyl-alpha-L-rhamnopyranoside)) has been shown to be an RSK selective inhibitor. However, the K-i for SL0101 is 1 mu M with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5 ''-n-propyl group on the rhamnose that has >40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5 ''-n-propyl analogue to inhibit MCF-7 proliferation was only 2-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5 ''-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.