3α,12α-diethoxy-5β-cholan-24-oic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 3α,12α-diethoxy-5β-cholan-24-oic acid
• 英文别名: (4R)-4-[(3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-diethoxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• 化学式: C₂₈H₄₈O₄
• 分子量: 448.687
• InChiKey: PWEMSZPFUPHOMP-BJICXTOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  去氧胆酸 、 碘乙烷 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 73.0h， 以52%的产率得到3α-ethoxy-12α-hydroxy-5β-cholan-24-oic acid
  参考文献：
  名称：

  Deoxycholic acid as a molecular scaffold for tyrosyl-DNA phosphodiesterase 1 inhibition: A synthesis, structure–activity relationship and molecular modeling study

  摘要：

  Para-Bromoanilides of deoxycholic acid with various functional groups on the steroid scaffold were designed as promising tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors. Tdp1 is a DNA repair enzyme, involved in removing DNA damage caused by topoisomerase I poisons; an important class of anticancer drugs. Thus, reducing the activity of Tdp1 can increase the efficacy of anticancer drugs in current use. Inhibitory activity in the low micromolar and submicromolar concentrations was observed with 3,12-dimethoxy para-bromoanilide 17 being the most active with an IC₅₀ value of 0.27 μM. The activity of N-methyl para-bromoanilides was 3-4.8 times lower than of the corresponding para-bromoanilides. Increased potency of the ligands was seen with higher molecular weight and log P values. The ligands were evaluated for their cytotoxic potential in a panel of tumor cell lines; all were nontoxic to the A549 pulmonary adenocarcinoma cell line. However, derivatives containing a hydroxyl group at the 12th position were more toxic than their 12-hydroxyl group counterparts (acetoxy-, oxo- and methoxy- group) against HCT-116 human colon and HepG2 hepatocellular carcinomas. In addition, an N-methyl substitution led to an increase in toxicity for the HCT-116 and HepG2 cell lines. The excellent activity as well as low cytotoxicity, derivative 17 can be considered as a lead compound for further development.

  DOI：

  10.1016/j.steroids.2020.108771

文献信息

• US4624919A
  申请人：——

  公开号：US4624919A

  公开（公告）日：1986-11-25
• US4782019A
  申请人：——

  公开号：US4782019A

  公开（公告）日：1988-11-01
• Deoxycholic acid as a molecular scaffold for tyrosyl-DNA phosphodiesterase 1 inhibition: A synthesis, structure–activity relationship and molecular modeling study
  作者：Oksana V. Salomatina、Irina I. Popadyuk、Alexandra L. Zakharenko、Olga D. Zakharova、Arina A. Chepanova、Nadezhda.S. Dyrkheeva、Nina I. Komarova、Jóhannes Reynisson、Rashid O. Anarbaev、Nariman F. Salakhutdinov、Olga I. Lavrik、Konstantin P. Volcho

  DOI：10.1016/j.steroids.2020.108771

  日期：2021.1

  Para-Bromoanilides of deoxycholic acid with various functional groups on the steroid scaffold were designed as promising tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors. Tdp1 is a DNA repair enzyme, involved in removing DNA damage caused by topoisomerase I poisons; an important class of anticancer drugs. Thus, reducing the activity of Tdp1 can increase the efficacy of anticancer drugs in current use. Inhibitory activity in the low micromolar and submicromolar concentrations was observed with 3,12-dimethoxy para-bromoanilide 17 being the most active with an IC₅₀ value of 0.27 μM. The activity of N-methyl para-bromoanilides was 3-4.8 times lower than of the corresponding para-bromoanilides. Increased potency of the ligands was seen with higher molecular weight and log P values. The ligands were evaluated for their cytotoxic potential in a panel of tumor cell lines; all were nontoxic to the A549 pulmonary adenocarcinoma cell line. However, derivatives containing a hydroxyl group at the 12th position were more toxic than their 12-hydroxyl group counterparts (acetoxy-, oxo- and methoxy- group) against HCT-116 human colon and HepG2 hepatocellular carcinomas. In addition, an N-methyl substitution led to an increase in toxicity for the HCT-116 and HepG2 cell lines. The excellent activity as well as low cytotoxicity, derivative 17 can be considered as a lead compound for further development.