4-(4-isopropoxybenzamido)-5-(4-(benzyloxy)phenyl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylate acid

• 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: 4-(4-isopropoxybenzamido)-5-(4-(benzyloxy)phenyl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylate acid
• 英文别名: 4-(4-isopropoxybenzamido)-1-(4-phenoxyphenyl)-5-(4-benzyloxyphenyl)pyrazole-3-carboxylic acid；1-(4-Phenoxyphenyl)-5-(4-phenylmethoxyphenyl)-4-[(4-propan-2-yloxybenzoyl)amino]pyrazole-3-carboxylic acid；1-(4-phenoxyphenyl)-5-(4-phenylmethoxyphenyl)-4-[(4-propan-2-yloxybenzoyl)amino]pyrazole-3-carboxylic acid
• 化学式: C₃₉H₃₃N₃O₆
• 分子量: 639.708
• InChiKey: AEJNGYMCEFEGCG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.6
• 重原子数：
  48
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-苯氧基苯肼盐酸盐 在 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 38.0h， 生成 4-(4-isopropoxybenzamido)-5-(4-(benzyloxy)phenyl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylate acid
  参考文献：
  名称：

  Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics

  摘要：

  No alpha-helical mimetic that exhibits Bd-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the alpha-helixes at their binding interfaces. Herein, we extracted a one-turn alpha-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn alpha-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

  DOI：

  10.1021/acs.jmedchem.5b01913

文献信息

• 一类1,5-二苯基吡唑-3-羧酸类化合物及其应 用
  申请人：大连理工大学

  公开号：CN105061315B

  公开（公告）日：2017-10-24

  本发明提供了一类1,5‑二苯基吡唑‑3‑羧酸类化合物及其应用，所述化合物具有通式I的结构，其中：R1选自‑H、卤素、C1～C6的饱和烷基或‑X1‑R4；R2选自H、卤素、C1～C6的饱和烷基或‑X2‑R5；R3选自H、‑NH2或‑NH‑CO‑Ph‑(o﹑m﹑p)R6；R6选自H、卤素、C1～C6的饱和烷基或‑O‑R7；X1和X2分别独立选自O或S；R4、R5和R7分别独立选自H、C1～C6的饱和烷基、苄基或C1～C6的饱和烷基取代的苯基。本发明的化合物同时模拟BH3‑only和p53TAD蛋白α‑螺旋，竞争性结合和拮抗Mcl‑1、Bcl‑2和MDM2蛋白，特异性引起肿瘤细胞凋亡，实现其作为抗癌化合物的应用。
• Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics
  作者：Ziqian Wang、Ting Song、Yingang Feng、Zongwei Guo、Yudan Fan、Wenjie Xu、Lu Liu、Anhui Wang、Zhichao Zhang

  DOI：10.1021/acs.jmedchem.5b01913

  日期：2016.4.14

  No alpha-helical mimetic that exhibits Bd-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the alpha-helixes at their binding interfaces. Herein, we extracted a one-turn alpha-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn alpha-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.