benzyl 5-bromomethyl-2-propoxybenzoate | 1259391-06-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 5-bromomethyl-2-propoxybenzoate
• 英文别名: Benzyl 5-(bromomethyl)-2-propoxybenzoate
• CAS: 1259391-06-4
• 化学式: C₁₈H₁₉BrO₃
• 分子量: 363.251
• InChiKey: RVHBGHZMALUWNG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  benzyl 5-bromomethyl-2-propoxybenzoate 在 吡啶 、 盐酸 、 manganese(IV) oxide 、 硼烷四氢呋喃络合物 、 氰基磷酸二乙酯 、 palladium 10% on activated carbon 、 盐酸羟胺 、 氢气 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， -50.0~20.0 ℃ 、500.01 kPa 条件下， 反应 8.0h， 生成
  参考文献：
  名称：

  Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility

  摘要：

  In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.

  DOI：

  10.1016/j.bmc.2013.02.003
• 作为产物：
  描述：

  benzyl 2-hydroxy-5-formylbenzoate 在 sodium tetrahydroborate 、 三溴化磷 、 potassium carbonate 作用下， 以 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 benzyl 5-bromomethyl-2-propoxybenzoate
  参考文献：
  名称：

  设计，合成和体外评估一系列α-取代的苯丙酸PPARγ激动剂，以进一步研究立体化学与活性之间的关系

  摘要：

  我们先前证明，α-苄基苯丙酸型PPARγ-选择性激动剂6表现出相反的立体化学-活性关系，即与结构上相比，（R）-对映体比（S）-对映体是更有效的PPARγ激动剂。类似的α-乙基苯基丙酸型PPAR激动剂。在此，我们分别设计，合成和评估了旋光性α-环己基甲基苯基丙酸衍生物7和α-苯乙基苯基丙酸衍生物8。有趣的是，α-环己基甲基衍生物显示出立体化学-活性关系的逆转[即（R）比（S）]，就像α-苄基衍生物一样，而α-苯乙基衍生物表现出“正常”关系[（S）比（R）更有效。这些结果表明，相对于羧基而言，β位上存在支链碳原子是逆转立体化学-活性关系的关键决定因素。

  DOI：

  10.1016/j.bmc.2012.08.061

文献信息

• Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry–activity relationship
  作者：Masao Ohashi、Izumi Nakagome、Jun-ichi Kasuga、Hiromi Nobusada、Kenji Matsuno、Makoto Makishima、Shuichi Hirono、Yuichi Hashimoto、Hiroyuki Miyachi

  DOI：10.1016/j.bmc.2012.08.061

  日期：2012.11

  stereochemistry–activity relationship, that is, the (R)-enantiomer is a more potent PPARγ agonist than the (S)-enantiomer, compared with structurally similar α-ethylphenylpropanoic acid-type PPAR agonists. Here, we designed, synthesized and evaluated the optically active α-cyclohexylmethylphenylpropanoic acid derivatives 7 and α-phenethylphenylpropanoic acid derivatives 8, respectively. Interestingly, α-cyclohexylmethyl

  我们先前证明，α-苄基苯丙酸型PPARγ-选择性激动剂6表现出相反的立体化学-活性关系，即与结构上相比，（R）-对映体比（S）-对映体是更有效的PPARγ激动剂。类似的α-乙基苯基丙酸型PPAR激动剂。在此，我们分别设计，合成和评估了旋光性α-环己基甲基苯基丙酸衍生物7和α-苯乙基苯基丙酸衍生物8。有趣的是，α-环己基甲基衍生物显示出立体化学-活性关系的逆转[即（R）比（S）]，就像α-苄基衍生物一样，而α-苯乙基衍生物表现出“正常”关系[（S）比（R）更有效。这些结果表明，相对于羧基而言，β位上存在支链碳原子是逆转立体化学-活性关系的关键决定因素。
• Design, Synthesis, and Structural Analysis of Phenylpropanoic Acid-Type PPARγ-Selective Agonists: Discovery of Reversed Stereochemistry−Activity Relationship
  作者：Masao Ohashi、Takuji Oyama、Izumi Nakagome、Mayumi Satoh、Yoshino Nishio、Hiromi Nobusada、Shuichi Hirono、Kosuke Morikawa、Yuichi Hashimoto、Hiroyuki Miyachi

  DOI：10.1021/jm101233f

  日期：2011.1.13

  Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-mediated transcription factor with roles in glucose, lipid, and lipoprotein homeostasis, and PPAR gamma ligands are expected have therapeutic potential in these as well as other areas We report here the design, synthesis, crystallographic analysis, and computational studies of alpha-benzylphenylpropanoic acid PPAR gamma agonists Interestingly, these compounds show a reversal of the stereochemistry-transactivation activity relationship observed with other phenylpropanoic acid ligands
• Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility
  作者：Masao Ohashi、Takuji Oyama、Endy Widya Putranto、Tsuyoshi Waku、Hiromi Nobusada、Ken Kataoka、Kenji Matsuno、Masakazu Yashiro、Kosuke Morikawa、Nam-ho Huh、Hiroyuki Miyachi

  DOI：10.1016/j.bmc.2013.02.003

  日期：2013.4

  In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.