Design and Synthesis of ?-O-Glucosylated 5-(Arylidene)-6-Aminouracils: Towards Water-Soluble 8-Aryl Xanthines as Effective Enzyme Inhibitors

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dc.contributor.authorPoslu, Ayse Halic
dc.contributor.authorErtik, Onur
dc.contributor.authorAbul, Nurgul
dc.contributor.authorTelli, Fatma Cetin
dc.contributor.authorGulcin, Ilhami
dc.contributor.authorKoz, Omer
dc.contributor.authorKoz, Gamze
dc.date.accessioned2024-08-31T07:49:49Z
dc.date.available2024-08-31T07:49:49Z
dc.date.issued2024
dc.departmentEge Üniversitesien_US
dc.description.abstract8-Aryl xanthines are selective enzyme inhibitors modified from naturally occurring methylxanthines. However, the low water solubility of substituted xanthines restricts their clinical applications. We developed a strategy to improve the water solubility of biologically privileged 8-aryl xanthines. A series of glucosylated 5-(arylidene)-6-aminouracil was synthesized as 8-aryl-1,3-dimethyl xanthine precursors and fully characterized with spectroscopic methods. Koenigs-Knorr reaction was used to synthesize beta-O-glucosylated aromatic aldehydes which were then reacted with 5,6-diamino-1,3-dimethyluracil to obtain the corresponding 5-(arylidene)-6-aminouracils. The strategy was validated by the ring-closing reaction of a beta-O-glucosylated 5-(arylidene)-6-aminouracil derivative with iodine (I-2) in dimethoxyethane. The water solubility of the glucosylated 8-aryl-1,3-dimethyl xanthine and its non-glycosylated counterpart was compared. Glucosylation improved the water solubility of the compound. The effect of glucosylation on the bioactivity of the compounds was investigated by measuring their inhibition effect on some common enzymes. The glucosylated 8-aryl xanthine demonstrated significantly better efficiency. Molecular docking was performed to elucidate the ligand-protein interactions. Since the target enzymes are primarily related to brain disorders, the blood-brain barrier (BBB) penetration ability of 8-aryl xanthine partners was investigated. According to adsorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, glucosylated 8-aryl xanthine was found to be BBB permeable.en_US
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [119Z876]en_US
dc.description.sponsorshipWe are grateful to the Scientific and Technological Research Council of Turkey (TUBITAK Project No. 119Z876) for financial support.en_US
dc.identifier.doi10.1002/slct.202401406
dc.identifier.issn2365-6549
dc.identifier.issue26en_US
dc.identifier.scopus2-s2.0-85197926078en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.urihttps://doi.org/10.1002/slct.202401406
dc.identifier.urihttps://hdl.handle.net/11454/105010
dc.identifier.volume9en_US
dc.identifier.wosWOS:001262680900001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherWiley-V C H Verlag Gmbhen_US
dc.relation.ispartofChemistryselecten_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240831_Uen_US
dc.subjectNitrogen Heterocyclesen_US
dc.subject8-Aryl Xanthineen_US
dc.subjectGlucosylationen_US
dc.subjectEnzymesen_US
dc.subjectMolecular Dockingen_US
dc.titleDesign and Synthesis of ?-O-Glucosylated 5-(Arylidene)-6-Aminouracils: Towards Water-Soluble 8-Aryl Xanthines as Effective Enzyme Inhibitorsen_US
dc.typeArticleen_US

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