(S)‐4‐(4‐chlorophenyl)‐4‐(1H‐indol‐3‐yl)‐4‐butan‐2‐one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)‐4‐(4‐chlorophenyl)‐4‐(1H‐indol‐3‐yl)‐4‐butan‐2‐one
• 英文别名: (4S)-4-(4-chlorophenyl)-4-(1H-indol-3-yl)butan-2-one
• 化学式: C₁₈H₁₆ClNO
• 分子量: 297.784
• InChiKey: ADSVBZBUKVOROK-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  32.9
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  吲哚 、 4-氯苯亚甲基丙酮 在 C₁₆H₂₈N₂O₃S 、 苯甲酸 作用下， 以 甲苯 为溶剂， 以82 %的产率得到(S)‐4‐(4‐chlorophenyl)‐4‐(1H‐indol‐3‐yl)‐4‐butan‐2‐one
  参考文献：
  名称：

  New enantioenriched β‐indolyl ketones as aromatase inhibitors: Unraveling heme–ligand interactions by MD simulation and MMPBSA analysis

  摘要：

  A series of enantioenriched β‐indolyl ketones as aromatase inhibitors (AI) is synthesized through the Michael‐type Friedel–Crafts alkylation of indole. A highly efficient bifunctionalized amino catalyst is developed to access structurally diverse β‐indolyl ketones in high yields (up to 91%) and excellent enantioselectivity (enantiomeric ratio up to 98:2). All the synthesized compounds demonstrated promising aromatase inhibitory potential, where ortho‐substituted analogs (3c and 3e) were found most active with IC₅₀ values of 0.68 and 0.90 µM, respectively. Both of these compounds exhibited significant cytotoxicity (IC₅₀= 0.34 and 0.37 µM) against the MCF‐7 breast cancer cell line in the (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide) assay. Molecular docking studies of the synthesized compounds demonstrate favorable binding interactions with the estrogens controlling CYP19A1 (3EQM) and metabolizing CYP3A4 (5VCC) enzymes. Molecular dynamic (MD) simulation analysis revealed the essentiality of heme–ligand interactions to build a stable protein–ligand complex. An average root mean square deviation of 0.35 nm observed during a 100‐ns MD simulation and binding free energy in the range of −190 to −227 kJ/mol calculated by g_mmpbsa analysis authenticated the stability of the 3c–3EQM complex. ADMET and drug‐likeness parameters supported the suitability of these indole derivatives as the drug lead to develop potent inhibitors for estrogen‐dependent breast cancer.

  DOI：

  10.1002/ardp.202400010

文献信息

• Organocatalytic Asymmetric Friedel−Crafts Alkylation of Indoles with Simple α,β-Unsaturated Ketones
  作者：Giuseppe Bartoli、Marcella Bosco、Armando Carlone、Fabio Pesciaioli、Letizia Sambri、Paolo Melchiorre

  DOI：10.1021/ol070309o

  日期：2007.3.1

  text]. The first general and highly enantioselective organocatalytic Friedel-Crafts alkylation of indoles with simple alpha,beta-unsaturated ketones has been accomplished. Central to these studies has been the identification of a new catalyst amine salt, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis.

  [结构：见文字]。已经完成了具有简单的α，β-不饱和酮的吲哚的第一个一般的和高对映选择性的有机催化弗里德-克来福特烷基化反应。这些研究的中心是鉴定新的催化剂胺盐，其中阳离子和阴离子都是手性的，对亚胺离子催化具有很高的反应性和选择性。
• Organocatalytic enantioselective indole alkylations of α,β-unsaturated ketones
  作者：Wei Chen、Wei Du、Lei Yue、Rui Li、Yong Wu、Li-Sheng Ding、Ying-Chun Chen

  DOI：10.1039/b616504d

  日期：——

  The C3-selective enantioselective Michael-type Friedel-Crafts alkylations of indoles with nonchelating alpha,beta-unsaturated alkyl ketones, catalysed by a chiral primary amine derived from natural cinchonine, were investigated. The reactions, in the presence of 30 mol% catalyst, were smoothly conducted at 0 to -20 degrees C. Moderate to good ee (47-89%) has been achieved.

  研究了由天然辛可宁衍生的手性伯胺催化的具有非螯合的α，β-不饱和烷基酮的吲哚的C3-选择性对映选择性迈克尔型弗瑞德-克拉夫茨烷基化反应。在30mol％催化剂的存在下，反应在0至-20℃下顺利进行。已经实现了中等至良好的ee（47-89％）。
• New enantioenriched <i>β</i>‐indolyl ketones as aromatase inhibitors: Unraveling heme–ligand interactions by MD simulation and MMPBSA analysis
  作者：Maira Hasnain Pasha、Humaira Yasmeen Gondal、Shanza Munir、Sami A. Alhussain、Magdi E. A. Zaki

  DOI：10.1002/ardp.202400010

  日期：——

  A series of enantioenriched β‐indolyl ketones as aromatase inhibitors (AI) is synthesized through the Michael‐type Friedel–Crafts alkylation of indole. A highly efficient bifunctionalized amino catalyst is developed to access structurally diverse β‐indolyl ketones in high yields (up to 91%) and excellent enantioselectivity (enantiomeric ratio up to 98:2). All the synthesized compounds demonstrated promising aromatase inhibitory potential, where ortho‐substituted analogs (3c and 3e) were found most active with IC₅₀ values of 0.68 and 0.90 µM, respectively. Both of these compounds exhibited significant cytotoxicity (IC₅₀= 0.34 and 0.37 µM) against the MCF‐7 breast cancer cell line in the (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide) assay. Molecular docking studies of the synthesized compounds demonstrate favorable binding interactions with the estrogens controlling CYP19A1 (3EQM) and metabolizing CYP3A4 (5VCC) enzymes. Molecular dynamic (MD) simulation analysis revealed the essentiality of heme–ligand interactions to build a stable protein–ligand complex. An average root mean square deviation of 0.35 nm observed during a 100‐ns MD simulation and binding free energy in the range of −190 to −227 kJ/mol calculated by g_mmpbsa analysis authenticated the stability of the 3c–3EQM complex. ADMET and drug‐likeness parameters supported the suitability of these indole derivatives as the drug lead to develop potent inhibitors for estrogen‐dependent breast cancer.