3-{[(16β,17β)-17-hydroxy-3-(2-hydroxyethyl)estra-1,3,5(10)-trien-16-yl]methyl}benzamide | 1318265-17-6

• 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: 3-{[(16β,17β)-17-hydroxy-3-(2-hydroxyethyl)estra-1,3,5(10)-trien-16-yl]methyl}benzamide
• 英文别名: 3-{[(17β)-17-hydroxy-3-(2-hydroxyethyl)estra-1(10),2,4-trien-16-yl]methyl}benzamide；3-[[(8R,9S,13S,14S,16R,17S)-17-hydroxy-3-(2-hydroxyethyl)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-16-yl]methyl]benzamide
• CAS: 1318265-17-6
• 化学式: C₂₈H₃₅NO₃
• 分子量: 433.591
• InChiKey: ICSHNMXTCQFKLA-OPRSCSRJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  83.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-{[(16β,17β)-17-hydroxy-3-(2-hydroxyethyl)estra-1,3,5(10)-trien-16-yl]methyl}benzamide 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 戴斯-马丁氧化剂 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 3-{[(16β,17β)-17-hydroxy-3-[2-(methylamino)-2-oxoethyl]estra-1(10),2,4-trien-16-yl]methyl}benzamide
  参考文献：
  名称：

  [EN] INHIBITORS OF 17ß-HSD1, 17ß-HSD3 AND 17ß-HSD10
  [FR] INHIBITEURS DE 17SS-HSD1, 17SS-HSD3 ET 17SS-HSD10

  摘要：

  该申请公开了17β羟基类固醇脱氢酶（17β HSD）类型1、3、10的抑制剂及其在癌症和其他疾病治疗中的使用（单独和组合使用）。17β HSD1抑制剂包括在C16处带有尼达-氨甲酰苯甲基取代基的雌二醇衍生物。17β HSD3/HSD10抑制剂包括在C3位置用磺胺基哌嗪取代的雄甾酮衍生物。还公开了既是17β HSD1又是17β HSD3抑制剂的化合物，其在C20处带有螺环吗啡基取代基。

  公开号：

  WO2012129673A1
• 作为产物：
  描述：

  (8R,9S,13S,14S)-13-methyl-3-vinyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one 在 sodium tetrahydroborate 、 palladium 10% on activated carbon 、 oxone 、 ammonium acetate 、 氢气 、 碳酸氢钠 、 potassium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 、 丙酮 、 乙腈 为溶剂， 反应 31.5h， 生成 3-{[(16β,17β)-17-hydroxy-3-(2-hydroxyethyl)estra-1,3,5(10)-trien-16-yl]methyl}benzamide
  参考文献：
  名称：

  Discovery of a Non-Estrogenic Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1 from 3-Substituted-16β-(m-carbamoylbenzyl)-estradiol Derivatives

  摘要：

  17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16 beta-(m-carbamoylbenzy1)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17 beta-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17 beta-HSD1 named 3-{[(16 beta,17 beta)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17 beta-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17 beta-HSD2, 17 beta-HSD7, 17 beta-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23h is a competitive and irreversible inhibitor of 17 beta-HSD1.

  DOI：

  10.1021/jm401639v

文献信息

• Development of a Gram-Scale Synthesis of PBRM, an Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1
  作者：René Maltais、Donald Poirier

  DOI：10.1021/acs.oprd.8b00402

  日期：2019.11.15

  PBRM with a high-HPLC-grade purity (99.7%) after recrystallization. Important improvements have been achieved in this sequence from previously reported routes (A and B). Notably, we used a palladium-catalyzed Suzuki–Miyaura cross-coupling reaction to rapidly install the requested C3 chain on estrone. Also, catalytic hydrogenation of the C16-enone was shortened by half using Pearlman’s catalyst. Finally

  致力于开发可靠的克级规模的3-[（16β，17β）-3-（2-溴乙基）-17-羟基雌二醇1,3,5（10）-三烯-16-基]甲基的克级合成}描述了苯甲酰胺（PBRM），这是一种有效的选择性17β-羟基类固醇脱氢酶的类固醇共价抑制剂。在本文开发的三种合成路线（C–E）中，路线E是最有效的路线，距市售雌酮仅六个化学步骤，总收率为13％，从而获得了具有HPLC级纯度的PBRM（99.7）重结晶后）。从先前报告的路线（A和B）开始，此顺序已实现了重要的改进。值得注意的是，我们使用钯催化的Suzuki-Miyaura交叉偶联反应将所需的C3链快速安装在雌酮上。还，使用Pearlman催化剂，C16-烯酮的催化加氢缩短了一半。最后，我们在序列的最后一步使用了通过乙醇脱氧进行的选择性溴化，以提供PBRM而不会使其羧酰胺官能团脱水，这是在其他途径中观察到的一个持久性问题。通过在乙腈中重结晶也获得了PBR
• Crucial Role of 3-Bromoethyl in Removing the Estrogenic Activity of 17β-HSD1 Inhibitor 16β-(<i>m</i>-Carbamoylbenzyl)estradiol
  作者：René Maltais、Diana Ayan、Donald Poirier

  DOI：10.1021/ml200093v

  日期：2011.9.8

  17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) represents a promising therapeutic target for breast cancer treatment. To reduce the undesirable estrogenic activity of potent 17 beta-HSD1 inhibitor 16 beta-(m-carbamoylbenzyl)estradiol (1) (IC(50) = 27 nM), a series of analogues with a small functionalized side chain at position 3 were synthesized and tested. The 3-(2-bromoethyl)-16 beta-(m-carbamoylbenzy1)-estra-1,3,5(10)-trien-17 beta-ol (5) was found to be a potent inhibitor (IC(50) = 68 nM) for the transformation of estrone (E1) into estradiol (E2) and, most importantly, did not stimulate the proliferation of estrogen-sensitive MCF-7 cells, suggesting no estrogenic activity. From these results, the crucial role of a bromoalkyl side chain at carbon 3 was identified for the first time. Thus, this new inhibitor represents a good candidate with an interesting profile suitable for further studies including pharmacokinetic and in vivo studies.