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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-V C H 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.
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    L-(+)-Tryptophan methyl ester derived polymeric microbeads as an efffiicient heterogeneous catalyst for green synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles
    (Tubitak Scientific & Technological Research Council Turkey, 2022) Poslu, Ayse Halic; Osman, Bilgen; Kaya, Yunus; Koz, Omer; Koz, Gamze
    The cross-linked microbeads with average diameter of 106-300 mu m, [poly(EGDMA-MATrp)], were obtained by copolymerization reaction of N-methacryloyl-L-(+)-tryptophan methyl ester (MATrp) with ethylene glycol dimethacrylate (EGDMA) and successfully applied as a heterogeneous catalyst in conjugate addition reaction of nitromethane to substituted 2-iminochromenes in aqueous media. A variety of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles has been synthesized in good yields. Polymeric microbeads were very durable and reused 5 times without a significant loss of activity. DFT calculations and experimental results revealed the significant role of Tr-Tr interactions as well as hydrogen bonding in the reaction mechanism.
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    Synthesis and biological evaluation of novel salicylidene uracils: Cytotoxic activity on human cancer cell lines and inhibitory action on enzymatic activity
    (John Wiley and Sons Inc, 2024) Poslu, Ayşe Halıç; Aslan, Şafak Esra; Koz, Gamze; Şentürk, Esra; Koz, Omer; Şentürk, Murat; Nalbantsoy, A. Ş.
    A series of salicylidene uracil (1–18) derived from 5-aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Nine out of eighteen derivatives (6–8, 10, 12–15, 18) are novel molecules synthesized for the first time in this work, and other derivatives were previously synthesized by our group. The compounds were characterized by Proton nuclear magnetic resonance, carbon nuclear magnetic resonance, fourier transform infrared spectroscopy, and elemental analysis. All compounds were tested for their in vitro cytotoxicity against PC-3 (human prostate adenocarcinoma), A549 (human alveolar adenocarcinoma), and SHSY-5Y (human neuroblastoma) cancer cell lines and the nontumorigenic HEK293 (human embryonic kidney cells) cell line. The 3,5-di-tert-butylsalicylaldehyde derived compound (8) was toxic to PC-3 human prostate adenocarcinoma cells, showing a promising IC50 value at 7.05 ± 0.76 ?M. The present study also aimed to evaluate the inhibitory effects of the compounds against several key enzymes, namely carbonic anhydrase I and II (CA I and CA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione reductase (GR), which are implicated in various global disorders, such as Alzheimer's disease, epilepsy, cancer, malaria, diabetes, and glaucoma. The inhibitory profiles of the tested compounds were assessed by determining their Ki values, which ranged from 2.96 to 9.24 nM for AChE, 3.78 to 12.57 nM for BChE, 8.42 to 25.74 nM for CA I, 7.24 to 19.74 nM for CA II, and 0.541 to 1.124 ?M for GR. Molecular docking studies were also performed for all compounds. Most derivatives exhibited much more effective inhibitory action compared with clinically used standards. Thus, our findings indicate that the salicylidene derivatives presented in this study are promising drug candidates that need further evaluation. © 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.