2-n-butyl-1,3-bis(4-methoxyphenyl)propane-1,3-dione | 322399-91-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: 2-n-butyl-1,3-bis(4-methoxyphenyl)propane-1,3-dione
• 英文别名: 2-Butyl-1,3-bis(4-methoxyphenyl)propane-1,3-dione
• CAS: 322399-91-7
• 化学式: C₂₁H₂₄O₄
• 分子量: 340.419
• InChiKey: SREUTJGNMABCSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-n-butyl-1,3-bis(4-methoxyphenyl)propane-1,3-dione 在 三溴化硼 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-[4-Butyl-5-(4-hydroxyphenyl)-2-phenylpyrazol-3-yl]phenol
  参考文献：
  名称：

  Pyrazole Ligands:  Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists

  摘要：

  We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ER alpha than on the ER beta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ER alpha -selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ER alpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ER alpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ER alpha. It also activates gene transcription only through ER alpha. Thus, this compound represents the first ER alpha -specific agonist. We investigated the molecular basis for the exceptional ER alpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ER alpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ER alpha has a smaller residue than ER beta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ER alpha.

  DOI：

  10.1021/jm000170m
• 作为产物：
  描述：

  己酸 在 PPA 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 2-n-butyl-1,3-bis(4-methoxyphenyl)propane-1,3-dione
  参考文献：
  名称：

  Pyrazole Ligands:  Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists

  摘要：

  We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ER alpha than on the ER beta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ER alpha -selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ER alpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ER alpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ER alpha. It also activates gene transcription only through ER alpha. Thus, this compound represents the first ER alpha -specific agonist. We investigated the molecular basis for the exceptional ER alpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ER alpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ER alpha has a smaller residue than ER beta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ER alpha.

  DOI：

  10.1021/jm000170m

文献信息

• Pyrazole Ligands:  Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists
  作者：Shaun R. Stauffer、Christopher J. Coletta、Rosanna Tedesco、Gisele Nishiguchi、Kathryn Carlson、Jun Sun、Benita S. Katzenellenbogen、John A. Katzenellenbogen

  DOI：10.1021/jm000170m

  日期：2000.12.1

  We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ER alpha than on the ER beta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ER alpha -selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ER alpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ER alpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ER alpha. It also activates gene transcription only through ER alpha. Thus, this compound represents the first ER alpha -specific agonist. We investigated the molecular basis for the exceptional ER alpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ER alpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ER alpha has a smaller residue than ER beta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ER alpha.