3-(3,17β-dihydroxy-estra-1,3,5(10)-trien-16β-ylmethyl)-benzamide | 1014704-30-3

• 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-(3,17β-dihydroxy-estra-1,3,5(10)-trien-16β-ylmethyl)-benzamide
• 英文别名: 16β-(m-carbamoylbenzyl)estradiol；3-{[(16β,17β)-3,17-dihydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide；CC-156；3-{[(9beta,14beta,16alpha,17alpha)-3,17-Dihydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide；3-[[(8R,9S,13S,14S,16R,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-16-yl]methyl]benzamide
• CAS: 1014704-30-3
• 化学式: C₂₆H₃₁NO₃
• 分子量: 405.537
• InChiKey: RSVOVHDOLNWYER-RYZVYYIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 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-(3,17β-dihydroxy-estra-1,3,5(10)-trien-16β-ylmethyl)-benzamide 在 ruthenium(III) trichloride hydrate sodium periodate 、 sodium hydroxide 作用下， 以 水 、 乙酸乙酯 、 丙酮 、 乙腈 为溶剂， 反应 5.36h， 生成 3-{[(16β,17β)-17-hydroxy-3-(2-hydroxyethoxy)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：

  3-(3,17β-dihydroxy-estra-1,3,5(10)-trien-16-ylidenemethyl)-benzamide 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以98%的产率得到3-(3,17β-dihydroxy-estra-1,3,5(10)-trien-16β-ylmethyl)-benzamide
  参考文献：
  名称：

  Estradiol and estrone C-16 derivatives as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Blocking of ER+ breast cancer cell proliferation induced by estrone

  摘要：

  Estrogens play an important role in the development of breast cancer. Inhibiting 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1)-the enzyme responsible for the last step in the biosynthesis of the most potent estrogen, estradiol (E-2)-would thus allow hindering the growth of estrogen-sensitive tumors. Based on a previous study identifying 16 beta-benzyl-E-2 (1) as a lead compound for developing inhibitors of the transformation of estrone (E-1) into E-2, we modified the benzyl group of 1 to improve its inhibitory activity. Three strategies were also devised to produce compounds with less residual estrogenic activity: (1) replacing the hydroxy group by a hydrogen at position 3 (C3); (2) adding a methoxy at C2; and (3) adding an alkylamide chain known to be antiestrogenic at C7. In order to test the inhibitory potency of the new compounds, we used the human breast cancer cell line T-47D, which exerts a strong endogenous 17 beta-HSD1 activity. In this intact cell model, 16 beta-m-carbamoylbenzyl-E-2 (4m) emerged as a potent inhibitor of 17 beta-HSD1 with an IC50 value of 44 nM for the transformation of [C-14]-E-1 (60 nM) into [C-14]-E-2 (24-h incubation). In another assay aimed at assessing the unwanted estrogenic activity, a 10-day treatment with 4m at a concentration of 0.5 mu M induced some proliferation (38%) of T-47D estrogen-sensitive (ER+) breast cancer cells. Interestingly, when 4m (0.5 mu M) was given with E-1 (0.1 nM) in a 10-day treatment, it blocked 62% of the T-47D cell proliferation induced by E-1 after its reduction to E-2 by 17 beta-HSD1. Thus, in addition to generating useful structure-activity relationships for the development of 17 beta-HSD1 inhibitors, our study demonstrates that using such inhibitors is a valuable strategy for reducing the level of E-2 and consequently its proliferative effect in T-47D ER+ breast cancer cells. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.007

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
• [EN] INHIBITORS OF 17ß-HSD1, 17ß-HSD3 AND 17ß-HSD10<br/>[FR] INHIBITEURS DE 17SS-HSD1, 17SS-HSD3 ET 17SS-HSD10
  申请人：UNIV LAVAL

  公开号：WO2012129673A1

  公开（公告）日：2012-10-04

  The present application discloses 17β hydroxy steroid dehydrogenase (17β HSD) type 1, 3, 10 inhibitors and use thereof (alone and in combination) in the treatment of cancer and other afflictions. 17β HSDl inhibitors include estradiol derivatives with a nieta-carbamoylbenzyl substituent at C 16. 17β HSD3/HSD10 inhibitors include androsterone derivatives substituted at the C3 position with a sulfonamide piperazine. Also disclosed are compounds that are inhibitors of both 17β HSDl and 17β HSD3 that have a spiro-morpholine substituent at C20.

  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。
• Chemical synthesis of C3-oxiranyl/oxiranylmethyl-estrane derivatives targeted by molecular modeling and tested as potential inhibitors of 17β-hydroxysteroid dehydrogenase type 1
  作者：Maxime Lespérance、Xavier Barbeau、Jenny Roy、René Maltais、Patrick Lagüe、Donald Poirier

  DOI：10.1016/j.steroids.2018.09.009

  日期：2018.12

  derivatives 11 and 15 were designed as 17&bgr;‐HSD1 inhibitors.Compounds 11 and 15 have been synthesized in a short and efficient route.A C3‐oxiranyl/oxiranylmethyl oxiranyl group did not alkylate the enzyme.The electrophilic group is not the only parameter to consider in generating a covalent inhibitor. ABSTRACT 17&bgr;‐Hydroxysteroid dehydrogenase type 1 (17&bgr;‐HSD1) is a promising therapeutic target

  HIGHLIGHTSC3-oxiranyl/oxiranylmethyl-estrane 衍生物 11 和 15 被设计为 17&bgr;-HSD1 抑制剂。化合物 11 和 15 已通过短而有效的途径合成。C3-oxiranyl/oxiranylmethyl oxiranyl 基团没有烷基化酶。 group 不是产生共价抑制剂时要考虑的唯一参数。摘要 17&bgr;-羟基类固醇脱氢酶 1 型 (17&bgr;-HSD1) 是一种很有前景的治疗靶点，已知在雌激素依赖性疾病（如乳腺癌和子宫内膜异位症）的进展中起关键作用。这种酶负责最有效的雌激素雌二醇 (E2) 生物合成的最后一步，它的抑制作用可以防止雌激素敏感肿瘤的生长。基于分子建模与对接实验，我们确定了两种有前景的 C3-环氧乙烷基/环氧乙烷基甲基-雌二醇衍生物，它们可以在 17&bgr;-HSD1 的催化位点竞争性地和不可逆地结合。它们
• Estradiol and estrone C-16 derivatives as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Blocking of ER+ breast cancer cell proliferation induced by estrone
  作者：Yannick Laplante、Christine Cadot、Michelle-Audrey Fournier、Donald Poirier

  DOI：10.1016/j.bmc.2007.11.007

  日期：2008.2.15

  Estrogens play an important role in the development of breast cancer. Inhibiting 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1)-the enzyme responsible for the last step in the biosynthesis of the most potent estrogen, estradiol (E-2)-would thus allow hindering the growth of estrogen-sensitive tumors. Based on a previous study identifying 16 beta-benzyl-E-2 (1) as a lead compound for developing inhibitors of the transformation of estrone (E-1) into E-2, we modified the benzyl group of 1 to improve its inhibitory activity. Three strategies were also devised to produce compounds with less residual estrogenic activity: (1) replacing the hydroxy group by a hydrogen at position 3 (C3); (2) adding a methoxy at C2; and (3) adding an alkylamide chain known to be antiestrogenic at C7. In order to test the inhibitory potency of the new compounds, we used the human breast cancer cell line T-47D, which exerts a strong endogenous 17 beta-HSD1 activity. In this intact cell model, 16 beta-m-carbamoylbenzyl-E-2 (4m) emerged as a potent inhibitor of 17 beta-HSD1 with an IC50 value of 44 nM for the transformation of [C-14]-E-1 (60 nM) into [C-14]-E-2 (24-h incubation). In another assay aimed at assessing the unwanted estrogenic activity, a 10-day treatment with 4m at a concentration of 0.5 mu M induced some proliferation (38%) of T-47D estrogen-sensitive (ER+) breast cancer cells. Interestingly, when 4m (0.5 mu M) was given with E-1 (0.1 nM) in a 10-day treatment, it blocked 62% of the T-47D cell proliferation induced by E-1 after its reduction to E-2 by 17 beta-HSD1. Thus, in addition to generating useful structure-activity relationships for the development of 17 beta-HSD1 inhibitors, our study demonstrates that using such inhibitors is a valuable strategy for reducing the level of E-2 and consequently its proliferative effect in T-47D ER+ breast cancer cells. (C) 2007 Elsevier Ltd. All rights reserved.
• Discovery of a Non-Estrogenic Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1 from 3-Substituted-16β-(<i>m</i>-carbamoylbenzyl)-estradiol Derivatives
  作者：René Maltais、Diana Ayan、Alexandre Trottier、Xavier Barbeau、Patrick Lagüe、Jean-Emmanuel Bouchard、Donald Poirier

  DOI：10.1021/jm401639v

  日期：2014.1.9

  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.