(2S,3R,4R,5S,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-6-propyltetrahydro-2H-pyran-3,4,5-triyl triacetate | 1266714-91-3

• 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,5S,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-6-propyltetrahydro-2H-pyran-3,4,5-triyl triacetate
• 英文别名: [(2S,3S,4R,5R,6S)-4,5-diacetyloxy-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-2-propyloxan-3-yl] acetate
• CAS: 1266714-91-3
• 化学式: C₂₉H₃₀O₁₃
• 分子量: 586.549
• InChiKey: HDCQFGSWWKAJHS-UDKWMEDXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  184
• 氢给体数：
  3
• 氢受体数：
  13

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 吡啶 、 4-二甲氨基吡啶 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 sodium tetrahydroborate 、 四氧化锇 、 cerium(III) chloride 、 palladium 10% on activated carbon 、 氢气 、 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 为溶剂， -90.0~20.0 ℃ 、101.33 kPa 条件下， 反应 26.0h， 生成 (2S,3R,4R,5S,6S)-2-((5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-6-propyltetrahydro-2H-pyran-3,4,5-triyl triacetate
  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

• SYNTHESIS AND IDENTIFICATION OF NOVEL RSK-SPECIFIC INHIBITORS
  申请人：Hecht Sidney M.

  公开号：US20120245112A1

  公开（公告）日：2012-09-27

  A composition comprising an SL0101 [kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside)] derivative compound that has enhanced ability to inhibit RSK activity, relative to the parent compound is provided. The compounds have utility for treating any disease or conditions characterized or associated with excess or undesirable RSK activity. For example the RSK inhibitors of the present invention can be used to reduce the proliferation of neoplastic cells or for inhibiting the establishment or maintenance of an intracellular pathogenic infection by pathogens whose pathogenicity derives in part from the pathogen's ability to impede endosomal/phagosomal maturation in the host cell.
• US9040673B2
  申请人：——

  公开号：US9040673B2

  公开（公告）日：2015-05-26
• 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.