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1
Enantiomeric 4-Acylamino-6-alkyloxy-2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy.对映体4-酰氨基-6-烷氧基-2-烷基硫代嘧啶作为潜在的A3腺苷受体拮抗剂：通过全套手性光谱进行高效液相色谱手性拆分和绝对构型确定
Chirality. 2016 May;28(5):434-40. doi: 10.1002/chir.22599. Epub 2016 Apr 20.
2
The A3 adenosine receptor: history and perspectives.A3 腺苷受体：历史与展望。
Pharmacol Rev. 2015;67(1):74-102. doi: 10.1124/pr.113.008540.
3
Allosteric modulators of human A2B adenosine receptor.人A2B腺苷受体的变构调节剂。
Biochim Biophys Acta. 2014 Mar;1840(3):1194-203. doi: 10.1016/j.bbagen.2013.12.021. Epub 2013 Dec 19.
4
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.国际基础和临床药理学联合会. LXXXI. 腺苷受体的命名和分类-更新。
Pharmacol Rev. 2011 Mar;63(1):1-34. doi: 10.1124/pr.110.003285. Epub 2011 Feb 8.
5
Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists.嘧啶衍生物作为强效和选择性的 A3 腺苷受体拮抗剂。
J Med Chem. 2011 Jan 27;54(2):457-71. doi: 10.1021/jm100843z. Epub 2010 Dec 27.
6
Recent developments in adenosine receptor ligands and their potential as novel drugs.腺苷受体配体的最新进展及其作为新型药物的潜力。
Biochim Biophys Acta. 2011 May;1808(5):1290-308. doi: 10.1016/j.bbamem.2010.12.017. Epub 2010 Dec 23.
7
Novel N2-substituted pyrazolo[3,4-d]pyrimidine adenosine A3 receptor antagonists: inhibition of A3-mediated human glioblastoma cell proliferation.新型 N2-取代的吡唑并[3,4-d]嘧啶腺苷 A3 受体拮抗剂：抑制 A3 介导的人神经胶质瘤细胞增殖。
J Med Chem. 2010 May 27;53(10):3954-63. doi: 10.1021/jm901785w.
8
Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3 adenosine receptor antagonists.4-氨基-6-羟基-2-巯基嘧啶衍生物作为新型、强效和选择性A3腺苷受体拮抗剂
J Med Chem. 2008 Mar 27;51(6):1764-70. doi: 10.1021/jm701159t. Epub 2008 Feb 13.
9
A new generation of adenosine receptor antagonists: from di- to trisubstituted aminopyrimidines.新一代腺苷受体拮抗剂：从二取代到三取代氨基嘧啶
Bioorg Med Chem. 2008 Mar 15;16(6):2741-52. doi: 10.1016/j.bmc.2008.01.013. Epub 2008 Jan 12.
10
2,4,6-trisubstituted pyrimidines as a new class of selective adenosine A1 receptor antagonists.作为一类新型选择性腺苷A1受体拮抗剂的2,4,6-三取代嘧啶
J Med Chem. 2004 Dec 16;47(26):6529-40. doi: 10.1021/jm049448r.

手性4-乙酰氨基-6-烷氧基-2-烷硫基嘧啶作为人A腺苷受体拮抗剂的对映选择性研究。

Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A adenosine receptor.

作者信息

Cosimelli Barbara, Greco Giovanni, Laneri Sonia, Novellino Ettore, Sacchi Antonia, Collina Simona, Rossi Daniela, Cosconati Sandro, Barresi Elisabetta, Taliani Sabrina, Trincavelli Maria Letizia, Martini Claudia

机构信息

Dipartimento di Farmacia , Università di Napoli "Federico II" , Via Domenico Montesano 49 , 80131 Naples , Italy . Email:

Dipartimento del Farmaco , Università di Pavia , Viale Torquato Taramelli 12 , 27100 Pavia , Italy.

出版信息

Medchemcomm. 2017 Nov 9;9(1):81-86. doi: 10.1039/c7md00375g. eCollection 2018 Jan 1.

DOI:10.1039/c7md00375g
PMID:30108902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6072526/
Abstract

Three A adenosine receptor (AR) antagonists () selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave us the chance to evaluate whether their higher lipophilicity, reduced conformational freedom and chirality might improve the potency towards the A AR. Racemic mixtures of were resolved using chiral HPLC methods and the absolute configurations of the enantiomers were assigned by chiroptical spectroscopy and density functional theory calculations. We measured the affinity for human A, A, A and A ARs of the racemic mixtures and the pure enantiomers of by radioligand competition binding experiments. Cell-based assays of the most potent enantiomers confirmed their A AR antagonist profiles. Our research led to the identification of ()- with high potency (0.5 nM) and selectivity as an A AR antagonist. Moreover we built a docking-model useful to design new pyrimidine derivatives.

摘要

我们从先前研究过的4-酰基氨基-6-烷氧基-2-烷基硫代嘧啶中选择了三种A腺苷受体（AR）拮抗剂，通过在其醚或硫醚侧链上插入一个甲基进行修饰。这些化合物使我们有机会评估其更高的亲脂性、降低的构象自由度和手性是否可能提高对A AR的效力。使用手性高效液相色谱法拆分了的外消旋混合物，并通过旋光光谱和密度泛函理论计算确定了对映体的绝对构型。我们通过放射性配体竞争结合实验测量了外消旋混合物和的纯对映体对人A、A、A和A ARs的亲和力。对最有效的对映体进行的基于细胞的测定证实了它们的A AR拮抗剂特征。我们的研究导致鉴定出（）-作为一种A AR拮抗剂具有高效力（0.5 nM）和选择性。此外，我们构建了一个对接模型，可用于设计新的嘧啶衍生物。