设计、合成及视网膜脱氢酶的体外评估一种选择性抑制剂。
Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes.
机构信息
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States.
出版信息
Bioorg Med Chem. 2018 Dec 1;26(22):5766-5779. doi: 10.1016/j.bmc.2018.10.009. Epub 2018 Oct 24.
Abstract
The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications.
摘要
视黄醛脱氢酶（RALDH）酶，RALDH1、RALDH2 和 RALDH3，催化视黄醛不可逆氧化为全反式视黄酸（ATRA）。尽管 RALDH 酶在胚胎发育、出生后生长和分化以及几种疾病状态中具有重要作用，但目前还没有专门针对这些同工酶的商业上可获得的抑制剂。我们在这里报告了小分子抑制剂二氯全反式视黄酮（DAR）（Summers 等人，2017 年）的开发和表征，它是 RALDH1、2 和 3 的不可逆抑制剂，有效地在纳摩尔范围内抑制 RALDH1、2 和 3，但对线粒体 ALDH2 没有抑制活性。这些结果为将 DAR 开发为各种实验和临床应用的特定 ATRA 合成抑制剂提供了支持。
相似文献
1
Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes.设计、合成及视网膜脱氢酶的体外评估一种选择性抑制剂。
Bioorg Med Chem. 2018 Dec 1;26(22):5766-5779. doi: 10.1016/j.bmc.2018.10.009. Epub 2018 Oct 24.
2
Inhibitors of aldehyde dehydrogenases of the 1A subfamily as putative anticancer agents: Kinetic characterization and effect on human cancer cells.1A 亚家族醛脱氢酶抑制剂作为潜在的抗癌药物：动力学特征及其对人癌细胞的影响。
Chem Biol Interact. 2019 Jun 1;306:123-130. doi: 10.1016/j.cbi.2019.04.004. Epub 2019 Apr 5.
3
Identification of active retinaldehyde dehydrogenase isoforms in the postnatal human eye.产后人眼中活性视黄醛脱氢酶同工型的鉴定
PLoS One. 2015 Mar 20;10(3):e0122008. doi: 10.1371/journal.pone.0122008. eCollection 2015.
4
Expression of retinaldehyde dehydrogenase (RALDH)2 and RALDH3 but not RALDH1 in the developing anterior pituitary glands of rats.视黄醛脱氢酶（RALDH）2和RALDH3在大鼠发育中的垂体前叶表达，而RALDH1不表达。
Cell Tissue Res. 2007 Apr;328(1):129-35. doi: 10.1007/s00441-006-0345-7. Epub 2006 Dec 19.
5
Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity.发现具有改善葡萄糖代谢活性的香豆素类选择性醛脱氢酶 1A1 抑制剂。
Eur J Med Chem. 2020 Feb 1;187:111923. doi: 10.1016/j.ejmech.2019.111923. Epub 2019 Dec 3.
6
Recombinant class I aldehyde dehydrogenases specific for all-trans- or 9-cis-retinal.对全反式或9-顺式视黄醛具有特异性的重组I类醛脱氢酶。
J Biol Chem. 2002 May 17;277(20):17486-92. doi: 10.1074/jbc.M112445200. Epub 2002 Mar 6.
7
Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives.补骨脂素和香豆素衍生物对乙醛脱氢酶1/2家族的抑制作用。
J Med Chem. 2017 Mar 23;60(6):2439-2455. doi: 10.1021/acs.jmedchem.6b01825. Epub 2017 Mar 6.
8
Kinetic analysis of mouse retinal dehydrogenase type-2 (RALDH2) for retinal substrates.小鼠视网膜脱氢酶2型（RALDH2）对视网膜底物的动力学分析。
Biochim Biophys Acta. 2002 Apr 1;1596(1):156-62. doi: 10.1016/s0167-4838(02)00213-3.
9
RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma.RALDH1 抑制在肝细胞癌中显示出免疫治疗疗效。
Cancer Immunol Res. 2024 Feb 2;12(2):180-194. doi: 10.1158/2326-6066.CIR-22-1023.
10
Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse.视黄酸合成（RALDH）酶在小鼠胎儿发育和器官分化过程中的差异表达。
Mech Dev. 2002 Jan;110(1-2):165-71. doi: 10.1016/s0925-4773(01)00561-5.
引用本文的文献
1
Pet Wellness and Vitamin A: A Narrative Overview.宠物健康与维生素A：概述
Animals (Basel). 2024 Mar 25;14(7):1000. doi: 10.3390/ani14071000.
2
RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma.RALDH1 抑制在肝细胞癌中显示出免疫治疗疗效。
Cancer Immunol Res. 2024 Feb 2;12(2):180-194. doi: 10.1158/2326-6066.CIR-22-1023.
3
Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration.维甲酸抑制剂可减轻视网膜变性小鼠模型的视力丧失。
Sci Adv. 2022 Mar 18;8(11):eabm4643. doi: 10.1126/sciadv.abm4643.
4
A commentary on the paper: 'Evaluation of spice and herb as phytoderived selective modulators of human retinaldehyde dehydrogenases using a simple in vitro method'.一篇关于“利用简单的体外方法评价香料和草药作为人视黄醛脱氢酶植物源选择性调节剂”的评论。
Biosci Rep. 2022 Jan 28;42(1). doi: 10.1042/BSR20211522.
5
Retinaldehyde Dehydrogenase Inhibition-Related Adverse Outcome Pathway: Potential Risk of Retinoic Acid Synthesis Inhibition during Embryogenesis.视黄醛脱氢酶抑制相关不良结局途径：胚胎发育过程中视黄酸合成抑制的潜在风险。
Toxins (Basel). 2021 Oct 20;13(11):739. doi: 10.3390/toxins13110739.
6
Evaluation of spice and herb as phyto-derived selective modulators of human retinaldehyde dehydrogenases using a simple in vitro method.利用简单的体外方法评估香料和草药作为人视黄醛脱氢酶的植物来源选择性调节剂。
Biosci Rep. 2021 May 28;41(5). doi: 10.1042/BSR20210491.
本文引用的文献
1
Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.不可逆和可逆小分子抑制剂对 ALDH1A2 的抑制作用的结构基础。
ACS Chem Biol. 2018 Mar 16;13(3):582-590. doi: 10.1021/acschembio.7b00685. Epub 2018 Jan 3.
2
Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma.醛脱氢酶活性在神经母细胞瘤的侵袭性表型中起关键作用。
BMC Cancer. 2016 Oct 10;16(1):781. doi: 10.1186/s12885-016-2820-1.
3
Postnatal Chick Choroids Exhibit Increased Retinaldehyde Dehydrogenase Activity During Recovery From Form Deprivation Induced Myopia.出生后小鸡脉络膜在从形觉剥夺性近视恢复过程中视网膜醛脱氢酶活性增加。
Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4886-4897. doi: 10.1167/iovs.16-19395.
4
Kinetic characterization and regulation of the human retinaldehyde dehydrogenase 2 enzyme during production of retinoic acid.视黄酸生成过程中人类视网膜醛脱氢酶2的动力学特性及调控
Biochem J. 2016 May 15;473(10):1423-31. doi: 10.1042/BCJ20160101. Epub 2016 Mar 21.
5
Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues.结构、生化和计算研究揭示细胞毒性柔红霉素类似物选择性抑制醛脱氢酶 1A1 的机制。
Angew Chem Int Ed Engl. 2015 Nov 9;54(46):13550-4. doi: 10.1002/anie.201505749. Epub 2015 Sep 16.
6
Inflammation rapidly modulates the expression of ALDH1A1 (RALDH1) and vimentin in the liver and hepatic macrophages of rats in vivo.炎症可迅速调节体内大鼠肝脏和肝巨噬细胞中 ALDH1A1（RALDH1）和波形蛋白的表达。
Nutr Metab (Lond). 2014 Nov 25;11:54. doi: 10.1186/1743-7075-11-54. eCollection 2014.
7
Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner.对小鼠体内乙醛脱氢酶1A（ALDH1A）进行药理抑制会以组织特异性方式降低全反式维甲酸的浓度。
Biochem Pharmacol. 2015 Jun 1;95(3):177-92. doi: 10.1016/j.bcp.2015.03.001. Epub 2015 Mar 9.
8
Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors.鉴定两种不同结构类型的选择性醛脱氢酶 1A1 抑制剂。
J Med Chem. 2015 Feb 26;58(4):1964-75. doi: 10.1021/jm501900s. Epub 2015 Feb 10.
9
Diethylaminobenzaldehyde is a covalent, irreversible inactivator of ALDH7A1.二乙氨基苯甲醛是一种对醛脱氢酶7A1具有共价、不可逆作用的抑制剂。
ACS Chem Biol. 2015 Mar 20;10(3):693-7. doi: 10.1021/cb500977q. Epub 2015 Jan 6.
10
Single amino acid polymorphism in aldehyde dehydrogenase gene superfamily.醛脱氢酶基因超家族的单个氨基酸多态性。
Front Biosci (Landmark Ed). 2015 Jan 1;20(2):335-76. doi: 10.2741/4313.
Zotero 插件