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Trifluorinated Pyrimidine-Based A(2B) Antagonists: Optimization and Evidence of Stereospecific Recognition
Univ Santiago De Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain;Univ Santiago De Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain.
Univ Santiago De Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain;Univ Santiago De Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0002-4951-9220
Univ Santiago De Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain;Univ Santiago De Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain.
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2019 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 20, p. 9315-9330Article in journal (Refereed) Published
Abstract [en]

We report the identification of two subsets of fluorinated nonxanthine A(2B) adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA(2B) affinity (K-i < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA(2B) receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA(2B) receptor.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 62, no 20, p. 9315-9330
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Medicinal Chemistry
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URN: urn:nbn:se:uu:diva-396965DOI: 10.1021/acs.jmedchem.9b01340ISI: 000492801800027PubMedID: 31557025OAI: oai:DiVA.org:uu-396965DiVA, id: diva2:1369770
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Swedish Research CouncileSSENCE - An eScience CollaborationAvailable from: 2019-11-13 Created: 2019-11-13 Last updated: 2019-11-13Bibliographically approved

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Jespers, WillemGutiérrez-de-Terán, Hugo

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