methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)propanoate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)propanoate
• 英文别名: Methyl 3-(5-amino-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propanoate；methyl 3-(5-amino-1,3-dioxoisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propanoate
• 化学式: C₂₀H₂₀N₂O₆
• 分子量: 384.389
• InChiKey: RPOHNDGOZDRWKA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)propanoate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 丙酮 为溶剂， 生成 methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)propanoate
  参考文献：
  名称：

  Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

  摘要：

  子宫松弛对早产至关重要。有人提出将磷酸二酯酶-4（PDE-4）抑制剂作为催产药。某些沙利度胺类似物是 PDE-4 抑制剂。本研究旨在评估两种沙利度胺类似物的子宫舒张特性，即 3-（4-硝基邻苯二甲酰亚胺基）-3-（3,4-二甲氧基苯基）-丙酸甲酯（4NO2PDPMe）和 3-（4-氨基邻苯二甲酰亚胺基）-3-（3,4-二甲氧基苯基）-丙酸甲酯（4NO2PDPMe）、和 3-（4-氨基邻苯二甲酰亚胺基）-3-（3，4-二甲氧基苯基）-丙酸甲酯（4APDPMe），并在离体妊娠人类子宫肌组织的自发阶段性收缩、K+ 诱导的强直性收缩和 Ca2+ 诱导的收缩的功能研究中与罗利普仑进行了比较。在 HeLa 细胞中对 cAMP 的积累进行了量化。在人子宫肌细胞（UtSMCs）中评估了 PDE-4B2 和磷酸化肌球蛋白轻链（pMLC）的存在，以及沙利度胺类似物对催产素诱导的 pMLC 的影响。沙利度胺类似物对自发收缩和强直收缩具有浓度依赖性抑制作用，并抑制 Ca2+ 诱导的反应。4APDPMe和罗利普仑对强直性收缩的抑制作用相同（IC50 = 125 ± 13.72 和 98.45 ± 8.86 µM）。罗利普仑和沙利度胺类似物对自发性收缩和强直性收缩的抑制作用相同。这两种类似物都以浓度依赖的方式增加了 cAMP 的积累（p < 0.05），并诱导了 UtSMCs 中催产素诱导的 pMLC 亚细胞定位的变化。沙利度胺类似物对妊娠人子宫肌组织收缩的抑制作用可能是由于它们的PDE-4抑制作用和作为钙通道阻滞剂的新机制。

  DOI：

  10.3390/molecules21101332

文献信息

• Two thalidomide analogs induce persistent estrous behavior and inhibit uterus contractility in rats: The central role of cAMP
  作者：E. Fernández-Martínez、F.J. Lima-Hernández、M. García-Juárez、R. Domínguez-Ordóñez、S. Tapia-Hernández、M.I. Ortiz、K.L. Hoffman、P. Gómora-Arrati、O. González-Flores

  DOI：10.1016/j.neulet.2019.134612

  日期：2020.1

  The effects of 4NO(2)PDPMe and 4APDPMe, which are thalidomide (Tha) analogs that act as selective phosphodiesterase (PDE-4) inhibitors, on estrous behavior (lordosis and proceptive behaviors) and on uterine contraction were studied in ovariectomized (OVX) estrogen-primed Sprague Dawley (SD) and in intact non-pregnant Wistar rats, respectively. We found that intracerebroventricular (ICV) infusion of either 4NO(2)PDPMe or 4APDPMe (20 to 80 pg) stimulated intense lordosis and proceptive behavior in response to mounts from a sexually active male, within the first 4 h after infusion, and persisting for up to 24 h. Inhibitors of the progesterone receptor (RU486, administered subcutaneously), the estrogen receptor (tamoxifen, ICV), the adenylate cyclase (AC)/ cyclic AMP (cAMP)/protein kinase A (PKA) pathway (administered ICV), and the mitogen activated protein kinase (MAPK) pathway (administered ICV) significantly decreased lordosis and proceptive behavior induced by Tha analogs. Uterine contractility studies showed that Tha analogs inhibited both the K+- and the Ca2+-induced tonic contractions in rat uterus. Tha analogs were equally effective, but 4APDPMe was more potent than 4NO(2)PDPMe. These results strongly suggest the central role of cAMP in both processes, sexual behavior, and uterine relaxation, and suggest that Tha analogs may also act as Ca2+-channel blockers.
• Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade
  作者：Eduardo Fernández-Martínez、Héctor Ponce-Monter、Luis Soria-Jasso、Mario Ortiz、José-Antonio Arias-Montaño、Guillermo Barragán-Ramírez、Cynthia Mayén-García

  DOI：10.3390/molecules21101332

  日期：——

  Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K+-induced tonic, and Ca2+-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

  子宫松弛对早产至关重要。有人提出将磷酸二酯酶-4（PDE-4）抑制剂作为催产药。某些沙利度胺类似物是 PDE-4 抑制剂。本研究旨在评估两种沙利度胺类似物的子宫舒张特性，即 3-（4-硝基邻苯二甲酰亚胺基）-3-（3,4-二甲氧基苯基）-丙酸甲酯（4NO2PDPMe）和 3-（4-氨基邻苯二甲酰亚胺基）-3-（3,4-二甲氧基苯基）-丙酸甲酯（4NO2PDPMe）、和 3-（4-氨基邻苯二甲酰亚胺基）-3-（3，4-二甲氧基苯基）-丙酸甲酯（4APDPMe），并在离体妊娠人类子宫肌组织的自发阶段性收缩、K+ 诱导的强直性收缩和 Ca2+ 诱导的收缩的功能研究中与罗利普仑进行了比较。在 HeLa 细胞中对 cAMP 的积累进行了量化。在人子宫肌细胞（UtSMCs）中评估了 PDE-4B2 和磷酸化肌球蛋白轻链（pMLC）的存在，以及沙利度胺类似物对催产素诱导的 pMLC 的影响。沙利度胺类似物对自发收缩和强直收缩具有浓度依赖性抑制作用，并抑制 Ca2+ 诱导的反应。4APDPMe和罗利普仑对强直性收缩的抑制作用相同（IC50 = 125 ± 13.72 和 98.45 ± 8.86 µM）。罗利普仑和沙利度胺类似物对自发性收缩和强直性收缩的抑制作用相同。这两种类似物都以浓度依赖的方式增加了 cAMP 的积累（p < 0.05），并诱导了 UtSMCs 中催产素诱导的 pMLC 亚细胞定位的变化。沙利度胺类似物对妊娠人子宫肌组织收缩的抑制作用可能是由于它们的PDE-4抑制作用和作为钙通道阻滞剂的新机制。