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    Design and Synthesis of ?-O-Glucosylated 5-(Arylidene)-6-Aminouracils: Towards Water-Soluble 8-Aryl Xanthines as Effective Enzyme Inhibitors
    (Wiley-V C H Verlag Gmbh, 2024) Poslu, Ayse Halic; Ertik, Onur; Abul, Nurgul; Telli, Fatma Cetin; Gulcin, Ilhami; Koz, Omer; Koz, Gamze
    8-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.
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    Discovery of a Uracil-Derived Small Organic Ligand with Cytotoxic Effect on Human PC-3 Cell Lines via Apoptosis
    (Wiley - VCH Verlag Gmbh, 2024) Poslu, Ayse Halic; Balaban, Rumeysa; Nalbantsoy, Ayse; Ertik, Onur; Cecener, Gulsah; Koz, Omer; Koz, Gamze
    A series of novel 6-amino-5-salicylidene uracils (1-19) were efficiently synthesized from the condensation reaction of 5,6-diamino-1,3-dimethyluracil with substituted salicylaldehydes. The structural characterization of the compounds was performed with spectroscopic methods and elemental analysis. All compounds were evaluated for their in vitro cytotoxic activity against PC-3 (human prostate adenocarcinoma), A549 (human alveolar adenocarcinoma) and SHSY-5Y (human neuroblastoma) cancer cell lines. 3,5-di-tert-Butylsalicylaldehyde derived salicylideneuracil (6ASU-8) showed promising cytotoxic activity against PC-3 cells with an IC50 value of 1.53 +/- 1.01 mu M, compared to doxorubicin, which had an IC50 value of 3.77 +/- 1.34 mu M. 6ASU-8 induced cell cycle arrest at the G2/M phase and promoted apoptosis in PC-3 cells (p<0.05*). Molecular docking results supported the experimental data, indicating that 6ASU-8 is more effective than doxorubicin. Additionally, in silico ADME analysis revealed that 6ASU-8 possesses acceptable predictive physicochemical properties.