异恶唑并嘧啶作为新型ΔF508-CFTR校正剂
Isoxazolopyrimidines as Novel ΔF508-CFTR Correctors.
作者信息
Yu Gui Jun, Yang Baoxue, Verkman A S, Kurth Mark J
机构信息
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
出版信息
Synlett. 2010 Apr 1;2010(7):1063-1066. doi: 10.1055/s-0029-1219781.
Abstract
Using a cell-based high-throughput screen, we identified isoxazolo[5,4-]pyrimidines as novel small-molecule correctors of the cystic fibrosis mutant protein ΔF508-CFTR. 22 Isoxazolo[5,4-]pyrimidine analogues were synthesized and tested. Synthesis of the key intermediate, 5-amino-3-arylisoxazole-4-carboxamide, was accomplished by nitrile oxide cycloaddition to (2-amino-1-cyano-2-oxoethyl)sodium. Formation of 3-arylisoxazolo-[5,4-]pyrimidin-4(5)-one and chlorination gave 4-chloro-3-arylisoxazolo[5,4-]pyrimidine. Finally, functionalization at C-4 of the pyrimidine ring by nucleophilic substitution gave the targeted isoxazolo[5,4-]pyrimidines. Six of the reported analogues had low micromolar potency for increasing halide transport in ΔF508-CFTR cells.
摘要
通过基于细胞的高通量筛选，我们鉴定出异恶唑并[5,4 - ]嘧啶为囊性纤维化突变蛋白ΔF508 - CFTR的新型小分子校正剂。合成并测试了22种异恶唑并[5,4 - ]嘧啶类似物。关键中间体5 - 氨基 - 3 - 芳基异恶唑 - 4 - 甲酰胺的合成是通过腈氧化物与(2 - 氨基 - 1 - 氰基 - 2 - 氧代乙基)钠进行环加成反应来完成的。3 - 芳基异恶唑并[5,4 - ]嘧啶 - 4(5) - 酮的形成和氯化反应得到4 - 氯 - 3 - 芳基异恶唑并[5,4 - ]嘧啶。最后，通过亲核取代在嘧啶环的C - 4位进行官能化反应得到目标异恶唑并[5,4 - ]嘧啶。所报道的类似物中有六种在增加ΔF508 - CFTR细胞中卤化物转运方面具有低微摩尔效力。
相似文献
1
Isoxazolopyrimidines as Novel ΔF508-CFTR Correctors.异恶唑并嘧啶作为新型ΔF508-CFTR校正剂
Synlett. 2010 Apr 1;2010(7):1063-1066. doi: 10.1055/s-0029-1219781.
2
Correctors enhance maturation of DeltaF508 CFTR by promoting interactions between the two halves of the molecule.校正剂通过促进分子两半部分之间的相互作用来增强DeltaF508囊性纤维化跨膜传导调节因子的成熟。
Biochemistry. 2009 Oct 20;48(41):9882-90. doi: 10.1021/bi9004842.
3
Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein DeltaF508-CFTR.设计并合成囊性纤维化突变蛋白 DeltaF508-CFTR 的混合型增强校正激动剂。
Bioorg Med Chem Lett. 2010 Jan 1;20(1):87-91. doi: 10.1016/j.bmcl.2009.11.020. Epub 2009 Nov 13.
4
Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product.校正剂和增强剂挽救截短型W1282X-囊性纤维化跨膜传导调节因子（CFTR）翻译产物的功能。
J Biol Chem. 2017 Jan 20;292(3):771-785. doi: 10.1074/jbc.M116.764720. Epub 2016 Nov 28.
5
Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein.评估融合吡咯并噻唑系统作为突变 CFTR 蛋白的校正剂。
Molecules. 2021 Feb 26;26(5):1275. doi: 10.3390/molecules26051275.
6
Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain.发现新型强效ΔF508-CFTR 校正剂，靶向核苷酸结合域。
EMBO Mol Med. 2013 Oct;5(10):1484-501. doi: 10.1002/emmm.201302699. Epub 2013 Aug 27.
7
Dynasore inhibits removal of wild-type and DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) from the plasma membrane.dynasore抑制野生型和ΔF508囊性纤维化跨膜传导调节因子（CFTR）从质膜上的移除。
Biochem J. 2009 Jul 15;421(3):377-85. doi: 10.1042/BJ20090389.
8
Functional fluorescently labeled bithiazole ΔF508-CFTR corrector imaged in whole body slices in mice.功能荧光标记双噻唑 ΔF508-CFTR 校正剂在小鼠整体切片中的成像。
Bioconjug Chem. 2011 Dec 21;22(12):2593-9. doi: 10.1021/bc2004457. Epub 2011 Nov 18.
9
Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3-d]pyrimidines for the Potential Treatment of Cystic Fibrosis.纠正ΔF508-囊性纤维化跨膜传导调节因子（CFTR）蛋白的新靶点：四氢吡啶并[4,3-d]嘧啶用于囊性纤维化潜在治疗的合成、药理学及药物代谢动力学评价
J Med Chem. 2015 Dec 24;58(24):9697-711. doi: 10.1021/acs.jmedchem.5b00771. Epub 2015 Dec 7.
10
Novel amino-carbonitrile-pyrazole identified in a small molecule screen activates wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator in the absence of a cAMP agonist.在小分子筛选中发现的新型氨基腈-吡唑在没有 cAMP 激动剂的情况下激活野生型和 ΔF508 囊性纤维化跨膜电导调节剂。
Mol Pharmacol. 2013 Sep;84(3):384-92. doi: 10.1124/mol.113.086348. Epub 2013 Jun 20.
引用本文的文献
1
Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-]pyrimidin-4(5)-one Scaffold.具有异恶唑并[5,4 - ]嘧啶 - 4(5)-酮骨架的新型选择性吲哚胺2,3-双加氧酶1（IDO1）抑制剂。
Pharmaceuticals (Basel). 2021 Mar 15;14(3):265. doi: 10.3390/ph14030265.
2
Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure.囊性纤维化的创新疗法：从治疗到治愈之路。
Mol Diagn Ther. 2019 Apr;23(2):263-279. doi: 10.1007/s40291-018-0372-6.
3
Molecular basis of cystic fibrosis: from bench to bedside.囊性纤维化的分子基础：从实验室到临床
Ann Transl Med. 2018 Sep;6(17):334. doi: 10.21037/atm.2018.06.48.
4
The rapid generation of isothiocyanates in flow.流动相中异硫氰酸酯的快速生成。
Beilstein J Org Chem. 2013 Aug 8;9:1613-9. doi: 10.3762/bjoc.9.184. eCollection 2013.
5
Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings.含稠合芳环的3-芳基异恶唑的合成改进
Tetrahedron. 2012 Dec 16;68(50):10360-10364. doi: 10.1016/j.tet.2012.09.084. Epub 2012 Sep 25.
本文引用的文献
1
Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.CFTR增强剂VX-770对体外CF气道上皮细胞功能的挽救作用
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. doi: 10.1073/pnas.0904709106. Epub 2009 Oct 21.
2
Chloride channels as drug targets.作为药物靶点的氯离子通道
Nat Rev Drug Discov. 2009 Feb;8(2):153-71. doi: 10.1038/nrd2780. Epub 2008 Jan 19.
3
Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy.用于囊性纤维化治疗的强效s-顺式锁定双噻唑校正剂，可纠正囊性纤维化跨膜传导调节因子的细胞加工过程。
J Med Chem. 2008 Oct 9;51(19):6044-54. doi: 10.1021/jm800533c. Epub 2008 Sep 13.
4
4'-Methyl-4,5'-bithiazole-based correctors of defective delta F508-CFTR cellular processing.基于4'-甲基-4,5'-联噻唑的缺陷型ΔF508-CFTR细胞加工校正剂。
Bioorg Med Chem Lett. 2008 Apr 15;18(8):2610-4. doi: 10.1016/j.bmcl.2008.03.037. Epub 2008 Mar 16.
5
CFTR function and prospects for therapy.囊性纤维化跨膜传导调节因子的功能及治疗前景。
Annu Rev Biochem. 2008;77:701-26. doi: 10.1146/annurev.biochem.75.103004.142532.
6
Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer.新型表皮生长因子受体抑制剂的放射性碘化作为乳腺癌分子成像潜在的单光子发射计算机断层显像剂
Bioorg Med Chem. 2007 Jun 15;15(12):3974-80. doi: 10.1016/j.bmc.2007.04.008. Epub 2007 Apr 10.
7
A spiroisoxazolinoproline-based amino acid scaffold for solid phase and one-bead-one-compound library synthesis.一种基于螺异恶唑啉脯氨酸的氨基酸支架，用于固相和单珠单化合物库的合成。
J Comb Chem. 2007 Jan-Feb;9(1):143-57. doi: 10.1021/cc060090p.
8
CFTR chloride channel drug discovery--inhibitors as antidiarrheals and activators for therapy of cystic fibrosis.囊性纤维化跨膜传导调节因子（CFTR）氯通道药物研发——作为止泻药的抑制剂及用于治疗囊性纤维化的激活剂
Curr Pharm Des. 2006;12(18):2235-47. doi: 10.2174/138161206777585148.
9
Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress.通过周期性剪切应力调节正常和囊性纤维化气道表面液体量
Annu Rev Physiol. 2006;68:543-61. doi: 10.1146/annurev.physiol.68.072304.112754.
10
Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.小分子对人囊性纤维化气道原代培养物中DeltaF508-CFTR转运和门控的挽救作用
Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1117-30. doi: 10.1152/ajplung.00169.2005. Epub 2006 Jan 27.
Zotero 插件