Acetaldehyd-N₁-(p-chlorbenzoyl)-p-methoxy-phenylhydrazon | 13815-59-3

• 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: Acetaldehyd-N₁-(p-chlorbenzoyl)-p-methoxy-phenylhydrazon
• 英文别名: 4-chloro-N'-ethylidene-N-(4-methoxyphenyl)benzohydrazide；4-Chlor-1,4-cyclohexadien-1-carbonsaeure-2-ethyliden-1-(p-methoxyphenyl)-hydrazid；4-chloro-N-(ethylideneamino)-N-(4-methoxyphenyl)benzamide
• CAS: 13815-59-3
• 化学式: C₁₆H₁₅ClN₂O₂
• 分子量: 302.76
• InChiKey: VTSSCGPIJYGEPE-UHFFFAOYSA-N

物化性质

• 熔点：
  92-95 °C
• 沸点：
  451.7±55.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  41.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Acetaldehyd-N₁-(p-chlorbenzoyl)-p-methoxy-phenylhydrazon 在 盐酸 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 生成 吲哚美辛
  参考文献：
  名称：

  Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer

  摘要：

  Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.

  DOI：

  10.1021/jm3017656
• 作为产物：
  描述：

  4-甲氧基苯肼盐酸盐 在 sodium hydroxide 作用下， 以 吡啶 为溶剂， 生成 Acetaldehyd-N₁-(p-chlorbenzoyl)-p-methoxy-phenylhydrazon
  参考文献：
  名称：

  Surborg, Arzneimittel-Forschung/Drug Research, 1980, vol. 30, # 8 A, p. 1384 - 1391

  摘要：

  DOI：

文献信息

• Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3
  作者：Marco L. Lolli、Irene M. Carnovale、Agnese C. Pippione、Weixiao Y. Wahlgren、Davide Bonanni、Elisabetta Marini、Daniele Zonari、Margherita Gallicchio、Valentina Boscaro、Parveen Goyal、Rosmarie Friemann、Barbara Rolando、Renzo Bagnati、Salvatore Adinolfi、Simonetta Oliaro-Bosso、Donatella Boschi

  DOI：10.1021/acsmedchemlett.8b00484

  日期：2019.4.11

  Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer.