methyl (R)-2-[1-(biphenyl-4-ylmethyl)-4-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]acetate | 1528534-36-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl (R)-2-[1-(biphenyl-4-ylmethyl)-4-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]acetate
• CAS: 1528534-36-2
• 化学式: C₂₇H₃₂N₂O₄
• 分子量: 448.562
• InChiKey: YVBGVISSBRAHPF-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.04
• 重原子数：
  33.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  66.92
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  methyl (R)-2-[1-(biphenyl-4-ylmethyl)-4-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]acetate 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 16.17h， 以96%的产率得到(R)-2-[1-(Biphenyl-4-ylmethyl)-4-(cyclohexylmethyl)piperazin-2-yl]ethanol
  参考文献：
  名称：

  Synthesis, Pharmacological Evaluation, and σ₁ Receptor Interaction Analysis of Hydroxyethyl Substituted Piperazines

  摘要：

  Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. sigma receptor affinity was recorded using receptor material from both animal and human origin, sigma(1) affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yliethanol (7c) revealed the highest affinity at human sigma(1) receptors (K-i = 6.8 nM). The potent a, receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC50 values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the a, receptor was analyzed in detail using the 3D homology model of the sigma(1) receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human a, receptor.

  DOI：

  10.1021/jm401707t
• 作为产物：
  描述：

  在 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 2.5h， 生成 methyl (R)-2-[1-(biphenyl-4-ylmethyl)-4-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]acetate
  参考文献：
  名称：

  刚性与灵活性：这是σ问题1受体的配体亲和活动？

  摘要：

  从（S）-或（R）-天冬氨酸开始的手性池合成中制备立体异构体2,5-二氮杂双环[2.2.2]辛烷14和15。合成的关键步骤是（二氧杂哌嗪基）乙酸酯8的Dieckmann相似环化反应，该过程涉及用Me 3 SiCl捕获中间的半缩酮阴离子。所述σ 1亲和力使用来自动物（豚鼠）膜制备物和人来源的测试。双环化合物的结合通过分子动力学模拟基于所述σ的3D同源性模型分析1受体。在σ中观察到的K i值之间的良好相关性1种测定法和计算出的自由结合能，再加上对四个关键配体/受体相互作用的鉴定，可以形成结构亲和力关系。在具有七个人类肿瘤细胞系的体外抗肿瘤测定中，双环化合物选择性抑制细胞系A427的生长，这是由于凋亡的诱导所致。在该测定中，所述化合物表现得像已知σ 1受体拮抗剂氟哌啶醇。

  DOI：

  10.1021/acs.jmedchem.6b00585

文献信息

• Involvement of apoptosis and autophagy in the death of RPMI 8226 multiple myeloma cells by two enantiomeric sigma receptor ligands
  作者：Katharina Korpis、Frauke Weber、Stefanie Brune、Bernhard Wünsch、Patrick J. Bednarski

  DOI：10.1016/j.bmc.2013.11.033

  日期：2014.1

  Over-expression of sigma receptors by many tumor cell lines makes ligands for these receptors attractive as potential chemotherapeutic drugs. Enantiomeric piperazines (S)-4 and (R)-4 were prepared as potential sigma-receptor ligands in a chiral pool synthesis starting from (S)- and (R)-aspartate. Both compounds showed high affinities for the sigma(1) and sigma(2) receptors. In the human multiple myeloma cell line RPMI 8226, a line expressing high levels of sigma receptors, both compounds inhibited cell proliferation with IC50 values in the low mu M range. No chiral differentiation between either the sigma receptor binding affinity or the cytotoxicity of the two enantiomers was observed. Both compounds induced apoptosis, which was evidenced by nuclear condensation, binding of annexin-V to phosphatidylserine in the outer leaf of the cell membrane, cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1) and caspase-8 as well as the expression of bcl(2) family members bax, bad and bid. However, apoptosis appeared to be caspase independent. Increased levels of the phosphorylated form of the microtubule associated protein light chain 3-II (LC3-II), an autophagosome marker, gave evidence that both compounds induced autophagy. However, further data (e.g., treatment with wortmannin) indicate that autophagy is incomplete and not cytoprotective. Lipid peroxidation (LPO) was observed in RPMI 8226 cells treated with the two compounds, and the lipid antioxidant alpha-tocopherol attenuated LPO. Interestingly, alpha-tocopherol reduced significantly both apoptosis and autophagy induced by the compounds. These results provide evidence that, by initiating LPO and changes in mitochondrial membrane potential, both compounds induce apoptosis and autophagy in RPMI 8226 cells. (C) 2013 Elsevier Ltd. All rights reserved.