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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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    Structural characterization and biological evaluation of uracil-appended benzylic amines as acetylcholinesterase and carbonic anhydrase I and II inhibitors
    (Elsevier, 2023) Bulut, Zafer; Abul, Nurgul; Poslu, Ayse Halic; Gulcin, Ilhami; Ece, Abdulilah; Ercag, Erol; Koz, Gamze
    A series of novel uracil-appended benzylic amines were synthesized through reductive amination with moderate to good yields (30-84% yields). In situ prepared 5-(arylidene)-6-aminouracils with the condensation reaction between 5,6-diamino-1,3-dimethyluracil and substituted salicylaldehydes were reduced by excess sodium borohydride. All of the compounds were characterized using FT-IR, H-1 NMR, C-13 NMR spectroscopy and elemental analysis. The inhibition abilities of novel uracil-appended benzylic amines (1-9) were evaluated against acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and II) isoenzymes that are linked to some global disorders such as Alzheimer's disease (AD), epilepsy, diabetes and glaucoma. The compounds exhibited inhibition profiles with K-i values ranging from 2.28 +/- 0.41 nM to 5.25 +/- 0.75 nM for AChE, 36.10 +/- 5.22-110.31 +/- 54.81 nM for hCA I and 16.33 +/- 4.91-72.03 +/- 28.86 for hCA II. Tacrine was used as a reference inhibitor for AChE and exhibited a K-i value of 2.59 +/- 0.92 nM against the AChE enzyme. On the other hand, Acetazolamide was used as a standard inhibitor towards hCA I and hCA II isoforms with K-i values of 31.38 +/- 8.56 nM and 18.72 +/- 1.67 nM, respectively. The results of enzyme inhibition associated with some global metabolic diseases indicate that novel uracil-appended benzylic amines may have the potential to develop new drugs to treat some common diseases such as Alzheimer's disease (AD), epilepsy and glaucoma. Molecular docking simulations were conducted to explain the binding interactions of compounds with AChE, hCA I and hCA II. Pharmacokinetic profiles were predicted to be within the acceptable ranges. (c) 2023 Elsevier B.V. All rights reserved.
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    Surface Decoration of Cellulose With Trifluoromethylphenyl Substituted Thiourea: A Robust Hydrogen-Bonding Catalyst in Conjunction With L-Proline for the Asymmetric Direct Mannich Reaction
    (Wiley, 2024) Poslu, Ayse Halic; Koz, Gamze
    Cellulose is one of the most abundant biopolymers in nature. Despite being the subject of research in various fields, it is not as famous as chitosan in catalyst design. Herein, a novel thiourea-functionalized cellulose (CTU-6) was synthesized as a robust hydrogen bonding catalyst with the degree of substitution (DS) of 0.84. CTU-6 was characterized using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), x-ray powder diffraction (XRD), proton nuclear magnetic resonance spectroscopy (1HNMR), solid-state cross-polarization magic angle spinning carbon-13 nuclear magnetic resonance (CP/MAS 13C-NMR), thermal gravimetric analysis (TGA) and elementel analysis. CTU-6 catalyzed the direct asymmetric Mannich reaction between acetone, aniline, and various aromatic aldehydes in cooperation with L-proline. The reaction exhibited excellent enantioselectivity, achieving up to 98% enantiomeric excess (ee) at room temperature. Incorporating trifluoromethylphenyl-substituted thiourea into the cellulose framework leverages its ability to form hydrogen bonds, thereby enabling precise control over the asymmetric induction. This study highlights the potential of cellulose-based catalysts in advancing asymmetric synthesis and their versatility in various organic reactions in cooperation with small chiral ligands. This synergy not only facilitates the efficient catalytic process but also improves the stereochemical outcomes of the reactions. This method underscores the importance of utilizing renewable and versatile cellulose materials in combination with chiral auxiliaries to achieve high levels of enantioselectivity.
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    Synthesis, spectroscopic analysis, quantum chemical calculations and in silico biological activity studies of a new series of 8-aryl xanthine
    (Elsevier, 2024) Bilkan, Mustafa Tugfan; Najeeb, Hamsa Abdullah; Poslu, Ayse Halic; Bilkan, Cigdem; Koz, Gamze
    Xanthines and its derivatives are important bronchodilator agents in treating asthma and bronchitis. In this work, four new 8 -aryl xanthine derivatives were synthesized and characterized using spectroscopic techniques (FT-IR, NMR) and elemental analysis. Density Functional Theory (DFT) approach is a reliable way to predict the physicochemical and biological properties of the structures. Investigations on the molecular structure, electronic and vibrational characteristics, UV -visible absorption bands, molecular electrostatic potential maps, and frontier molecular orbital analysis of 8 -aryl xanthines were performed using DFT/B3LYP level of theory with 6-311++G (d,p) basis set. The theoretical data and experimental observations were in good agreement. In addition, druglikeness, ADME, and toxicity parameters were calculated to reveal the biological potential of the compounds.