3β-(1H-1,2,4-triazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene | 1441047-13-7

• 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: 3β-(1H-1,2,4-triazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene
• 英文别名: 3β-(1Η-1,2,4-triazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene；[(3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] 1,2,4-triazole-1-carboxylate
• CAS: 1441047-13-7
• 化学式: C₂₉H₃₃N₅O₂
• 分子量: 483.613
• InChiKey: GIXXZKHGNJCPBI-QAKRQNAOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  36
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  74.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (3beta)-17-(1H-苯并咪唑-1-基)雄甾-5,16-二烯-3-醇 3-乙酸酯 在 甲醇 、 potassium hydroxide 作用下， 以 乙腈 为溶剂， 反应 4.5h， 生成 3β-(1H-1,2,4-triazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene
  参考文献：
  名称：

  Systematic Structure Modifications of Multitarget Prostate Cancer Drug Candidate Galeterone To Produce Novel Androgen Receptor Down-Regulating Agents as an Approach to Treatment of Advanced Prostate Cancer

  摘要：

  As part of our program to explore the influence of small structural modifications of our drug candidate 3 beta-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3 beta-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3 beta-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI(50) values of 0.87, 1.91, and 2.57 mu M, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.

  DOI：

  10.1021/jm400048v

文献信息

• [EN] ANDROGEN RECEPTOR DOWN-REGULATING AGENTS AND USES THEREOF<br/>[FR] AGENTS DE DIMINUTION DU RÉCEPTEUR DES ANDROGÈNES ET LEURS UTILISATIONS
  申请人：UNIV MARYLAND

  公开号：WO2014153215A8

  公开（公告）日：2015-11-05
• Systematic Structure Modifications of Multitarget Prostate Cancer Drug Candidate Galeterone To Produce Novel Androgen Receptor Down-Regulating Agents as an Approach to Treatment of Advanced Prostate Cancer
  作者：Puranik Purushottamachar、Abhijit M. Godbole、Lalji K. Gediya、Marlena S. Martin、Tadas S. Vasaitis、Andrew K. Kwegyir-Afful、Senthilmurugan Ramalingam、Zeynep Ates-Alagoz、Vincent C. O. Njar

  DOI：10.1021/jm400048v

  日期：2013.6.27

  As part of our program to explore the influence of small structural modifications of our drug candidate 3 beta-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3 beta-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3 beta-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI(50) values of 0.87, 1.91, and 2.57 mu M, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.