3-((E)-((8R,9S,13S,14S,17S)-3-(2-(benzyloxy)ethyl)-17-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-16-ylidene)methyl)benzamide | 1417621-07-8

• 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-((E)-((8R,9S,13S,14S,17S)-3-(2-(benzyloxy)ethyl)-17-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-16-ylidene)methyl)benzamide
• 英文别名: 3-{(E)-[(16E,17β)-3-[2-(benzyloxy)ethyl]-17-hydroxyestra-1,3,5(10)-trien-16-ylidene]methyl}benzamide
• CAS: 1417621-07-8
• 化学式: C₃₅H₃₉NO₃
• 分子量: 521.7
• InChiKey: LUOCKZCSNMQMGC-AOLIKXFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.46
• 重原子数：
  39.0
• 可旋转键数：
  7.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  72.55
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  3-((E)-((8R,9S,13S,14S,17S)-3-(2-(benzyloxy)ethyl)-17-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-16-ylidene)methyl)benzamide 在 四溴化碳 、 palladium 10% on activated carbon 、 氢气 、 三苯基膦 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 37.7h， 生成 PBRM
  参考文献：
  名称：

  Crucial Role of 3-Bromoethyl in Removing the Estrogenic Activity of 17β-HSD1 Inhibitor 16β-(m-Carbamoylbenzyl)estradiol

  摘要：

  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.

  DOI：

  10.1021/ml200093v
• 作为产物：
  描述：

  3-{(E)-[(16E)-3-[2-(benzyloxy)ethyl]-17-oxoestra-1,3,5(10)-trien-16-ylidene]methyl}benzamide 在 sodium tetrahydroborate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 3-((E)-((8R,9S,13S,14S,17S)-3-(2-(benzyloxy)ethyl)-17-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-16-ylidene)methyl)benzamide
  参考文献：
  名称：

  Crucial Role of 3-Bromoethyl in Removing the Estrogenic Activity of 17β-HSD1 Inhibitor 16β-(m-Carbamoylbenzyl)estradiol

  摘要：

  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.

  DOI：

  10.1021/ml200093v

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