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    Design, synthesis, and antiproliferative activities of novel thiazolyl-pyrazole hybrid derivatives
    (Springer Birkhauser, 2023) Kuzu, Burak; Erguc, Ali; Karakus, Fuat; Arzuk, Ege
    In this study, a series of derivatives of thiazolyl-pyrazole hybrid structures were designed to search for new heterocyclic compound-based antitumor agents. The designed target structures were synthesized with easy, practical, and efficient procedures. The antiproliferative effect of the synthesized compounds against cancer cell lines A549, MCF-7, and HepG2 was evaluated regarding inhibition concentration and selectivity index against healthy cell line CCD-34Lu. The results overall showed that the compounds had high antiproliferation against cancer cells compared to the doxorubicin-positive control. In particular, compound 11 A549 (SI: 3.58) and HepG2 (SI: 12.36) had high selectivity in cancer cell lines, while compounds 10h and 10o had high selectivity (SI: 10.74 for both) in MCF-7 cancer cell lines. The calculated theoretical pharmacokinetic properties revealed that they could be suitable drug candidates. In addition, in vitro test results indicate a correlation between the structure-activity relationships of the compounds. The various molecular modifications of thiazolyl-pyrazole hybrid compounds are promising for developing new anticancer drug candidates.
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    Mitochondrial Biotransformation of Drugs and other Xenobiotics
    (Bentham Science Publ Ltd, 2021) Orhan, Hilmi; Karakus, Fuat; Erguc, Ali
    In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.
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    Mitochondrial Impact of Organophosphate Pesticide-Induced Cardiotoxicity: An In Silico and In Vitro Study
    (Sage Publications Inc, 2024) Karakus, Fuat; Arzuk, Ege; Erguc, Ali
    Organophosphate pesticides are widely used; however, their use is limited due to neurotoxicity and, to a lesser extent, cardiotoxicity in humans. Given the high energy demands of cardiac muscle, which is characterized by a dense population of mitochondria, any damage to these organelles can exacerbate cardiotoxicity. This study aims to elucidate whether the cardiotoxic effects of organophosphate pesticides originate from mitochondrial dysfunction. To investigate this, in silico toxicogenomic analyses were performed using various tools, such as the Comparative Toxicogenomic Database, GeneMANIA, STRING, and Cytoscape. Results revealed that 11 out of the 13 WHO-recommended Class Ia organophosphate pesticides target genes associated with cardiotoxicity. Notably, three of these genes were mitochondrial, with catalase (CAT) being the common differentially expressed gene among parathion, methyl parathion, and phorate. Furthermore, protein-protein interaction analysis indicated a strong association between CAT and superoxide dismutase 2, mitochondrial (SOD2). Subsequently, isolated heart mitochondria were utilized to assess CAT and superoxide dismutase (SOD) activities in vitro. The findings demonstrated that at a concentration of 7.5 ng/mu L, both methyl parathion and phorate significantly decreased CAT activity by approximately 35%. Moreover, phorate reduced total SOD and SOD2 activities by 17% and 19%, respectively, at the same concentration. In contrast, none of the three organophosphate pesticides induced the opening of the mitochondrial permeability transition pore. These results suggest that the reduction in CAT and SOD2 activities, critical antioxidant enzymes, leads to the accumulation of reactive oxygen species within mitochondria, ultimately resulting in mitochondrial damage. This mechanism likely underlies the observed cardiotoxicity induced by these organophosphate pesticides.
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    Mitochondrial toxicity of selected natural compounds: in vitro assessment and in silico molecular docking and dynamics simulation
    (Taylor & Francis Ltd, 2024) Erguc, Ali; Albayrak, Gokay; Muhammed, Muhammed Tilahun; Karakus, Fuat; Arzuk, Ege
    Prangos uechtritzii Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate in vitro and in silico models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. In vitro results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The in silico study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.
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    Novel Pyrazole Derivatives Bearing Carbonitrile and Substituted Thiazole Moiety for Selective COX-2 Inhibition
    (Wiley-V C H Verlag Gmbh, 2024) Arzuk, Ege; Karakus, Fuat; Erguc, Ali; Kuzu, Burak
    In this study, a series of derivatives of pyrazole hybrid structures containing carbonitrile and substituted thiazole moiety were designed to search for selective COX-2 inhibition. The designed target structures were synthesized with easy, practical, and efficient procedures. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines for inhibition concentration and selectivity index. The results showed that the compounds have an inhibitory effect with higher selectivity towards COX-2 overall in both cell lines and moderate antiproliferative activity by targeting the breast cancer cell line MDA-MB-231. Among the 19 compounds synthesized (19 a-t), especially compound 19 m was found to be highly effective with COX-2 inhibition of 5.63 mu M in the NIH/3T3 cell line and 4.12 mu M in the MDA-MB-231 cell line. Moreover, molecular docking studies showed that the compounds indeed exhibited higher affinity for the COX-2 active site. The theoretical ADMET properties of the presented compounds were calculated, and the results showed that the compounds may have a more favorable pharmacokinetic effect profile than the selective COX-2 inhibitor Celecoxib, thus promising COX-2 inhibitor drug candidates for the future. A series of derivatives of pyrazole hybrid structures were designed to search for selective COX-2 inhibition. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines. Moreover, molecular docking, SAR, and ADMET studies showed that the compounds may have a more favorable pharmacokinetic profile, thus promising COX-2 inhibitor drug candidates for the future.image
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    Synthesis and Biological Evaluation of New Quinoline-Based Thiazolyl Hydrazone Derivatives as Potent Antifungal and Anticancer Agents
    (Bentham Science Publ Ltd, 2018) Erguc, Ali; Altintop, Mehlika Dilek; Atli, Ozlem; Sever, Belgin; Iscan, Gokalp; Gormus, Gozde; Ozdemir, Ahmet
    Background: In medicinal chemistry, thiazoles have gained great importance in anti-fungal and anticancer drug design and development. Objectives: The aim of this study was to synthesize new quinoline-based thiazolyl hydrazone derivatives and evaluate their anticandidal and anticancer effects. Methods: New thiazolyl hydrazone derivatives were evaluated for their anticandidal effects using disc diffusion method. Ames MPF assay was carried out to determine the genotoxicity of the most effective antifungal derivative. MTT assay was also performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, MCF7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines. Results: 4-(4-Fluorophenyl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (4) showed antifungal activity against Candida albicans and Candida krusei in the concentration of 1 mg/mL. In MTT and Ames MPF tests, it was determined that compound 4 did not show cytotoxic and genotoxic effects. MTT assay indicated that 4-(naphthalen-2-yl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (10) showed more selective anticancer activity than cisplatin against A549 and MCF-7 cell lines. Besides, 4-(4-chlorophenyl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (5) exhibited more selective anticancer activity than cisplatin against HepG2 cell line. Conclusion: Due to their high selectivity index, these compounds are considered as candidate compounds to participate in further research.