4’-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid | 1244012-15-4

• 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: 4’-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid
• 英文别名: 4'-[(5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]-biphenyl-2-carboxylic acid；2-[4-[(5-Bromo-2-propylbenzimidazol-1-yl)methyl]phenyl]benzoic acid
• CAS: 1244012-15-4
• 化学式: C₂₄H₂₁BrN₂O₂
• 分子量: 449.347
• InChiKey: QTTGIDDWMFMEJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4'-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile 在 水 、 potassium hydroxide 、 盐酸 作用下， 以 乙二醇 、 水 为溶剂， 反应 0.25h， 以73%的产率得到4’-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid
  参考文献：
  名称：

  Characterization of new PPARγ agonists: Benzimidazole derivatives—importance of positions 5 and 6, and computational studies on the binding mode

  摘要：

  In this and previous studies we investigated the importance of partial structures of Telmisartan on PPAR gamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl) methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d] imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPAR gamma DEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPAR gamma activation. An enhanced effect on PPAR gamma activation could be observed if lipophilic moieties are introduced in these positions. 4 '-[(2-Propyl-1H-naphtho[2,3-d] imidazol-1-yl) methyl] biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC50 of 0.26 mu M and the profile of a full agonist.Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.102

文献信息

• Synthesis and Characterization of Telmisartan‐Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia
  作者：Anna M. Schoepf、Stefan Salcher、Verena Hohn、Florina Veider、Petra Obexer、Ronald Gust

  DOI：10.1002/cmdc.202000092

  日期：2020.6.17

  New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator‐activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death‐modulating effects

  根除慢性粒细胞白血病 (CML) 中癌症干细胞的新策略包括伊马替尼与过氧化物酶体增殖物激活受体 γ (PPARγ) 配体的组合。最近，我们发现 PPARγ 部分激动剂替米沙坦是对伊马替尼治疗耐药的 K562 CML 细胞的有效敏化剂。在此，杂环核心对替米沙坦衍生铅 4'-((2-丙基-1 H-苯并[ d ]咪唑-1-基)甲基)-[1,1研究了'-联苯]-2-羧酸( 3 b )。受 HYL-6d 和选择性 PPARγ 配体 VSP-51 药效学的启发，苯并咪唑被咔唑或吲哚核心取代。结果表明 PPARγ 激活与耐药 CML 细胞对伊马替尼的敏感性之间没有相关性。咔唑或吲哚的 2-COOH 衍生物对 PPARγ 的活性较低，而苯并咪唑则显示出 60-100% 的活化率。在2-CO 2 CH 3衍生物中，只有铅的酯( 2b )轻微激活PPARγ。进一步观察到这种非细胞毒性2b 的致敏作用（80%