ethyl 1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxylate | 1447711-37-6

• 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: ethyl 1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxylate
• 英文别名: ethyl 5-(3-(4-hydroxy-3-methylphenyl)-pentan-3-yl)-1-ethyl-1H-pyrrole-2-carboxylate；ethyl-1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxylate；ethyl 1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1Hpyrrole-2-carboxylate；ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1-ethypyrrole-2-carboxylate
• CAS: 1447711-37-6
• 化学式: C₂₁H₂₉NO₃
• 分子量: 343.466
• InChiKey: CLQGNSIZXNPAEP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  25.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  51.46
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  ethyl 1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxylate 在 sodium tetrahydroborate 、 lithium hydroxide monohydrate 、 水 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium iodide 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 17.5h， 生成 2-(5-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-1-ethylpyrrole-2-carboxamido)acetic acid
  参考文献：
  名称：

  Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton

  摘要：

  In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC50: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC50: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC50 of 2.06 mu M and 0.307 mu M (tacalcitol: 2.07 mu M and 0.057 mu M) and showed no significant effect on serum calcium. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.09.015
• 作为产物：
  描述：

  吡咯-2-羧酸乙酯 在 palladium on activated charcoal 、 三氟化硼乙醚 、 甲酸铵 、 sodium hydride 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 ethyl 1-ethyl-5-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  非甾体维生素D3受体配体作为抗肿瘤剂的设计，合成和生物学评估。

  摘要：

  1α，25-二羟基维生素D3（1,25-（OH）2D3，也称为骨化三醇），维生素D3的活性形式，在癌症治疗中得到越来越多的认可。我们以前的工作表明，苯基-吡咯基戊烷类似物可模拟对天然类固醇配体1,25-（OH）2D3的几种癌细胞系的抗增殖活性。在这里，为了优化结构特征并发现更有效的衍生物，设计，合成和评估了一系列带有乙炔键的非甾体维生素D3受体（VDR）配体。它们中的大多数显示出中等至良好的结合亲和力和激动活性。尤其是，化合物19f对MCF-7和PC-3细胞表现出最大的抗增殖活性，其IC50值分别为1.80和5.35μM，与阳性对照1,25-（OH）2D3相当。

  DOI：

  10.1016/j.bmcl.2017.01.084

文献信息

• Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton
  作者：Cong Wang、Bin Wang、Lingjing Xue、Zisheng Kang、Siyuan Hou、Junjie Du、Can Zhang

  DOI：10.1021/acs.jmedchem.8b01165

  日期：2018.12.13

  Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor β1 (TGFβ1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR)

  肝纤维化的特征是细胞外基质（ECM）成分过多沉积，并导致肝功能受损。维生素D在肝纤维化的发展中起关键作用，因为它抑制转化生长因子β1（TGFβ1）诱导的肝星状细胞（HSC）中ECM的过度沉积。在这里，设计和合成了一系列具有苯基-吡咯烷基戊烷骨架的新型非甾体维生素D受体（VDR）激动剂。其中，包括15a在内的7种化合物在胶原蛋白沉积和纤维化基因表达中表现出更有效的抑制活性。组织学检查结果表明，化合物15a处理可防止由四氯化碳（CCl 4）注射到小鼠体内。此外，与阳性对照卡泊三醇和1,25（OH）2 D 3不同，化合物15a不会引起对神经，心脏和许多其他器官有毒的高钙血症。这些发现为使用非类固醇VDR调节剂治疗肝纤维化的药物发现提供了新颖的见解。
• Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents
  作者：Meixi Hao、Siyuan Hou、Lingjing Xue、Haoliang Yuan、Lulu Zhu、Cong Wang、Bin Wang、Chunming Tang、Can Zhang

  DOI：10.1021/acs.jmedchem.8b00106

  日期：2018.4.12

  The vitamin D (3) receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC50 values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.
• Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment
  作者：Zisheng Kang、Cong Wang、Yu Tong、Yanyi Li、Yi Gao、Siyuan Hou、Meixi Hao、Xiaolin Han、Bin Wang、Qianqian Wang、Can Zhang

  DOI：10.1021/acs.jmedchem.0c01197

  日期：2021.1.14
• Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer
  作者：Cong Wang、Bin Wang、Siyuan Hou、Lingjing Xue、Zisheng Kang、Junjie Du、Yanyi Li、Xuwentai Liu、Qianqian Wang、Can Zhang

  DOI：10.1016/j.ejmech.2018.12.024

  日期：2019.2

  Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC50 via the inhibition of cell cycle and induction of apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for cancer chemotherapy. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity
  作者：Zi-Sheng Kang、Cong Wang、Xiao-Lin Han、Bin Wang、Hao-Liang Yuan、Si-Yuan Hou、Mei-Xi Hao、Jun-Jie Du、Yan-Yi Li、An-Wei Zhou、Can Zhang

  DOI：10.1016/j.ejmech.2018.08.085

  日期：2018.9

  Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment. (C) 2018 Elsevier Masson SAS. All rights reserved.