{4-[(2β,3α,5α,17β)-3,17-dihydroxypregn-20-yn-2-yl]piperazin-1-yl}[(2S)-1-(naphthalen-2-ylcarbonyl)pyrrolidin-2-yl]methanone | 1228036-24-5

• 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: {4-[(2β,3α,5α,17β)-3,17-dihydroxypregn-20-yn-2-yl]piperazin-1-yl}[(2S)-1-(naphthalen-2-ylcarbonyl)pyrrolidin-2-yl]methanone
• 英文别名: {4-[(2β,3α,5α,17α)-3,17-dihydroxypregn-20-yn-2-yl]piperazin-1-yI}[(2S)-1-(naphthaIen-2-ylcarbonyl)pyrrolidin-2-yl]methanone；[4-[(2S,3S,5S,8R,9S,10S,13S,14S,17R)-17-ethynyl-3,17-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-2-yl]piperazin-1-yl]-[(2S)-1-(naphthalene-2-carbonyl)pyrrolidin-2-yl]methanone
• CAS: 1228036-24-5
• 化学式: C₄₁H₅₃N₃O₄
• 分子量: 651.89
• InChiKey: RHKJNYLBVOXWHB-OMHRILBISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  48
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  84.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2β-Piperazino-androsteron 在 甲醇 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 甲基锂 、 potassium carbonate 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 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-(naphthalen-2-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

文献信息

• New Diethylsilylacetylenic Linker for Parallel Solid-Phase Synthesis of Libraries of Hydroxy Acetylenic Steroid Derivatives with Improved Metabolic Stability
  作者：Amélie Talbot、René Maltais、Donald Poirier

  DOI：10.1021/co300034y

  日期：2012.6.11

  Acetylenic tertiary alcohols are well-known to be compounds that are biologically more stable than their corresponding secondary alcohols. The linkage of an acetylenic compound to a polymer support and further introduction of molecular diversity was found to be an interesting way to generate libraries of hydroxy acetylenic derivatives and thus potentially improve their biological properties. For the

  众所周知，乙炔叔醇是比它们相应的仲醇在生物学上更稳定的化合物。发现炔属化合物与聚合物载体的连接以及进一步引入分子多样性是产生羟基炔属衍生物的文库并因此潜在地改善其生物学性质的有趣方式。首次，我们描述了乙炔类固醇向聚苯乙烯-二乙基硅烷树脂的负载及其在21种类固醇衍生物的模型库的固相合成中的用途。通过连续添加氨基酸和羧酸来引入两个水平的分子多样性，然后通过酸性处理以高产率和纯度释放羟基炔类固醇，而无需进一步的纯化步骤。
• Solid-phase synthesis of libraries of ethynylated aminosteroid derivatives as potential antileukemic agents
  作者：Amélie Talbot、René Maltais、Lucie Carolle Kenmogne、Jenny Roy、Donald Poirier

  DOI：10.1016/j.steroids.2015.12.019

  日期：2016.3

  synthesis and the characterization of three libraries of ethynylated aminosteroid derivatives using the diethylacetylenic linker. We discuss their antiproliferative activities obtained in 2 leukemia cell lines (HL-60 and Jurkat), which results provided new structure-activity relationships. We also identified a new promising aminosteroid derivative with an azetidine moiety (compound B1) inhibiting 60% and

  众所周知，在 17α 位具有乙炔基的类固醇（叔醇）比其非乙炔基类似物（仲醇）更稳定。为了促进具有更好代谢稳定性的新药物的开发，我们开发了一种新的二乙基甲硅烷基炔属接头，使我们能够使用固相策略快速合成乙炔化类固醇衍生物库。为了说明其实用性，该接头用于扩展具有羟基炔烃模式的先导化合物的分子多样性，并有可能找到对白血病细胞系具有有趣细胞毒性活性的新化合物。在此，我们报告了使用二乙炔连接体的三个乙炔化氨基类固醇衍生物文库的化学合成和表征。我们讨论了它们在 2 个白血病细胞系（HL-60 和 Jurkat）中获得的抗增殖活性，这些结果提供了新的结构-活性关系。我们还鉴定了一种新的有前途的氨基类固醇衍生物，其具有氮杂环丁烷部分（化合物 B1），在 1 μM 时分别抑制 60% 和 75% 的 HL-60 和 Jurkat 细胞增殖。更一般地说，这些结果验证了二乙基甲硅烷基炔属接头对于有兴趣生成具有更好
• [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)
• 2-(N-Substituted Piperazinyl) Steroid Derivatives
  申请人：Poirier Donald

  公开号：US20110312926A1

  公开（公告）日：2011-12-22

  Novel chemical agents 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.

  本文描述了新型化学药剂。更具体地，本文揭示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。
• US8653054B2
  申请人：——

  公开号：US8653054B2

  公开（公告）日：2014-02-18