2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline | 1363386-55-3

• 物质功能分类: 医药中间体 - 喹啉类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
• 英文别名: 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline pinacol ester；2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone
• CAS: 1363386-55-3
• 化学式: C₁₇H₂₂BNO₃
• 分子量: 299.178
• InChiKey: DBPUJCOTOFBQID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.93
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 0.25h， 生成 BKI-1369
  参考文献：
  名称：

  基于吡唑并[3,4-d]嘧啶的蛋白激酶D抑制剂的设计，合成和生物学评估。

  摘要：

  蛋白激酶D（PKD）在各种癌症特征中的多重作用已被反复报道。因此，寻找新型PKD抑制剂及其作为抗肿瘤药的评价已引起了广泛的关注。在这项工作中，合成了新颖的基于吡唑并[3,4- d ]嘧啶的泛PKD抑制剂，其在位置1具有结构多样性，并对其生物学活性进行了评估。从3-IN-PP1（一种已知的PKD抑制剂，IC 50值在94-108 nM范围内）出发，发现化合物17m对PKD具有改善的生化抑制活性（IC 50 = 17-35 nM）。随后的细胞分析表明3-IN-PP1和17m抑制PKD依赖的cortactin磷酸化。此外，3-IN-PP1对PANC-1细胞显示出有效的抗增殖活性。最后，针对不同癌细胞系的筛选表明3-IN-PP1是一种有效且用途广泛的抗肿瘤药。

  DOI：

  10.1016/j.ejmech.2020.112638
• 作为产物：
  描述：

  6-溴-2-氯喹啉 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium ethanolate 、 potassium acetate 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
  参考文献：
  名称：

  基于吡唑并[3,4-d]嘧啶的蛋白激酶D抑制剂的设计，合成和生物学评估。

  摘要：

  蛋白激酶D（PKD）在各种癌症特征中的多重作用已被反复报道。因此，寻找新型PKD抑制剂及其作为抗肿瘤药的评价已引起了广泛的关注。在这项工作中，合成了新颖的基于吡唑并[3,4- d ]嘧啶的泛PKD抑制剂，其在位置1具有结构多样性，并对其生物学活性进行了评估。从3-IN-PP1（一种已知的PKD抑制剂，IC 50值在94-108 nM范围内）出发，发现化合物17m对PKD具有改善的生化抑制活性（IC 50 = 17-35 nM）。随后的细胞分析表明3-IN-PP1和17m抑制PKD依赖的cortactin磷酸化。此外，3-IN-PP1对PANC-1细胞显示出有效的抗增殖活性。最后，针对不同癌细胞系的筛选表明3-IN-PP1是一种有效且用途广泛的抗肿瘤药。

  DOI：

  10.1016/j.ejmech.2020.112638

文献信息

• Development of an Orally Available and Central Nervous System (CNS) Penetrant <i>Toxoplasma gondii</i> Calcium-Dependent Protein Kinase 1 (<i>Tg</i>CDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of <i>Toxoplasmosis</i>
  作者：Rama Subba Rao Vidadala、Kasey L. Rivas、Kayode K. Ojo、Matthew A. Hulverson、Jennifer A. Zambriski、Igor Bruzual、Tracey L. Schultz、Wenlin Huang、Zhongsheng Zhang、Suzanne Scheele、Amy E. DeRocher、Ryan Choi、Lynn K. Barrett、Latha Kallur Siddaramaiah、Wim G. J. Hol、Erkang Fan、Ethan A. Merritt、Marilyn Parsons、Gail Freiberg、Kennan Marsh、Dale J. Kempf、Vern B. Carruthers、Nina Isoherranen、J. Stone Doggett、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1021/acs.jmedchem.6b00760

  日期：2016.7.14

  New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.
• Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes
  作者：Rama Subba Rao Vidadala、Kayode K. Ojo、Steven M. Johnson、Zhongsheng Zhang、Stephen E. Leonard、Arinjay Mitra、Ryan Choi、Molly C. Reid、Katelyn R. Keyloun、Anna M.W. Fox、Mark Kennedy、Tiffany Silver-Brace、Jen C.C. Hume、Stefan Kappe、Christophe L.M.J. Verlinde、Erkang Fan、Ethan A. Merritt、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1016/j.ejmech.2013.12.048

  日期：2014.3

  Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein lcinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATPbinding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Development of <i>Toxoplasma gondii</i> Calcium-Dependent Protein Kinase 1 (<i>Tg</i>CDPK1) Inhibitors with Potent Anti-<i>Toxoplasma</i> Activity
  作者：Steven M. Johnson、Ryan C. Murphy、Jennifer A. Geiger、Amy E. DeRocher、Zhongsheng Zhang、Kayode K. Ojo、Eric T. Larson、B. Gayani K. Perera、Edward J. Dale、Panqing He、Molly C. Reid、Anna M. W. Fox、Natascha R. Mueller、Ethan A. Merritt、Erkang Fan、Marilyn Parsons、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1021/jm201713h

  日期：2012.3.8

  Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.