(2β,3α,5α)-3-hydroxy-2-(4-{[(2S)-1-(naphthalen-1-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one | 1228036-44-9

• 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: (2β,3α,5α)-3-hydroxy-2-(4-{[(2S)-1-(naphthalen-1-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one
• 英文别名: (2β,3α,5α)-3-hydroxy-2-(4-{[(2S)-1-(naphthaIen-1-yIcarbonyl)pyrroIidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one；(2S,3S,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-2-[4-[(2S)-1-(naphthalene-1-carbonyl)pyrrolidine-2-carbonyl]piperazin-1-yl]-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one
• CAS: 1228036-44-9
• 化学式: C₃₉H₅₁N₃O₄
• 分子量: 625.852
• InChiKey: URLIXSQMAXAGIC-QPDCKTOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  46
• 可旋转键数：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  81.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2β,3α,5α)-3-hydroxy-2-(4-{[(2S)-1-(naphthalen-1-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one 在 甲醇 、 甲基锂 、 potassium carbonate 作用下， 以 乙醚 为溶剂， 反应 8.0h， 生成 {4-[(2β,3α,5α,17β)-3,17-dihydroxypregn-20-yn-2-yl]piperazin-1-yl}[(2S)-1-(naphthalene-1-ylcarbonyl)pyrrolidin-2-yl]methanone
  参考文献：
  名称：

  Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5α-androstane-3α,17β-diol derivatives

  摘要：

  Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5 alpha-androstane-3 alpha, 17 beta-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2 beta and an ethinyl at position 17 alpha, showed very good antiproliferative activity among the five cancer cell lines studied (IC50 = 0.1, 0.1, 0.1, 2.0 and 1.1 mu M for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3 h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.09.026
• 作为产物：
  描述：

  tert-Butyl-1(naphthalene-1-ylcarbonyl)-L-Prolinate 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 水 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (2β,3α,5α)-3-hydroxy-2-(4-{[(2S)-1-(naphthalen-1-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one
  参考文献：
  名称：

  Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5α-androstane-3α,17β-diol derivatives

  摘要：

  Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5 alpha-androstane-3 alpha, 17 beta-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2 beta and an ethinyl at position 17 alpha, showed very good antiproliferative activity among the five cancer cell lines studied (IC50 = 0.1, 0.1, 0.1, 2.0 and 1.1 mu M for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3 h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.09.026

文献信息

• [EN] 2-(N-SUBSTITUTED PIPERAZINYL) STEROID DERIVATIVES<br/>[FR] DÉRIVÉS DE STÉROÏDES DE TYPE 2-(PIPÉRAZINYLE N-SUBSTITUÉ)
  申请人：UNIV LAVAL

  公开号：WO2010060215A1

  公开（公告）日：2010-06-03

  Novel chemical agents of Formula I are described herein. More specifically, 2-(N-substituted piperazinyl) pregnane and 2-(N-substituted piperazinyl) androstane derivatives exhibiting cytotoxicity on a variety of cancer cell lines are disclosed herein. (I)

  本文描述了化学式I的新型化学试剂。更具体地，本文披露了对多种癌细胞系表现出细胞毒性的2-(N-取代哌嗪基)孕酮和2-(N-取代哌嗪基)雄烷衍生物。 (I)