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Öğe Synthesis, structural investigations, DNA/BSA interactions, molecular docking studies, and anticancer activity of a new 1,4-disubstituted 1,2,3-triazole derivative(American Chemical Society, 2023) Göktürk, Tolga; Sakallı Çetin, Esin; Hökelek, Tuncer; Pekel, Hanife; Şensoy, Özge; Aksu, Ebru Nur; Güp, RamazanWe report herein a new 1,2,3-triazole derivative, namely, 4-(( 1-( 3,4-dichlorophenyl)-1H-1,2,3- triazol- 4-yl)methoxy)-2-hydroxybenzaldehyde, which was synthesized by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The structure of the compound was analyzed using Fourier transform infrared spectroscopy (FTIR), H-1 NMR, C-13 NMR, UV-vis, and elemental analyses. Moreover, X- ray crystallography studies demonstrated that the compound adapted a monoclinic crystal system with the P2(1)/c space group. The dominant interactions formed in the crystal packing were found to be hydrogen bonding and van der Waals interactions according to Hirshfeld surface (HS) analysis. The volume of the crystal voids and the percentage of free spaces in the unit cell were calculated as 152.10 A(3) and 9.80%, respectively. The evaluation of energy frameworks showed that stabilization of the compound was dominated by dispersion energy contributions. Both in vitro and in silico investigations on the DNA/bovine serum albumin (BSA) binding activity of the compound showed that the CT-DNA binding activity of the compound was mediated via intercalation and BSA binding activity was mediated via both polar and hydrophobic interactions. The anticancer activity of the compound was also tested by the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using human cell lines including MDA-MB-231, LNCaP, Caco-2, and HEK293. The compound exhibited more cytotoxic activity than cisplatin and etoposide on Caco-2 cancer cell lines with an IC50 value of 16.63 +/- 0.27 mu M after 48 h. Annexin V suggests the induction of cell death by apoptosis. Compound 3 significantly increased the loss of mitochondrial membrane potential (MMP) levels in Caco-2 cells, and the reactive oxygen species (ROS) assay proved that compound 3 could induce apoptosis by ROS generation.Öğe Inhibition of SARS-CoV-2 main protease: A repurposing study that targets the dimer interface of the protein(Taylor and Francis Ltd., 2022) Pekel, Hanife; İlter, Metehan; Şensoy, ÖzgeCoronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. Herein, we aimed at having a holistic understanding of conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (Mpro) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of apo and ?-ketoamide 13b-bound Mpro homodimer. Analysis of trajectories pertaining to apo Mpro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by ?-ketoamide 13b on the catalytic dyad of Mpro. Furthermore, ZINC23881687 stably interacted with catalytically important residues Glu166 and Ser1 and the target site throughout the simulation. However, it gave positive binding energy, presumably, due to displaying higher flexibility that might dominate the entropic term, which is not included in the MM-PBSA method. Finally, ZINC20425029, whose mode of action was different, modulated dynamical properties of catalytically important residue, Ala285. As such, this study presents valuable findings that might be used in the development of novel therapeutics against Mpro. Communicated by Ramaswamy H. Sarma.Öğe Mechanistic insight into impact of phosphorylation on the enzymatic steps of farnesyltransferase(Wiley, 2022) Pekel, Hanife; Güzel, Mustafa; Şensoy, ÖzgeFarnesyltransferase (FTase) is a heterodimeric enzyme, which catalyzes covalent attachment of the farnesyl group to target proteins, thus coordinating their trafficking in the cell. FTase has been demonstrated to be highly expressed in cancer and neurological diseases; hence considered as a hot target for therapeutic purposes. However, due to the nonspecific inhibition, there has been only one inhibitor that could be translated into the clinic. Importantly, it has been shown that phosphorylation of the alpha-subunit of FTase increases the activity of the enzyme in certain diseases. As such, understanding the impact of phosphorylation on dynamics of FTase provides a basis for targeting a specific state of the enzyme that emerges under pathological conditions. To this end, we performed 18 mu s molecular dynamics (MD) simulations using complexes of (non)-phosphorylated FTase that are representatives of the farnesylation reaction. We demonstrated that phosphorylation modulated the catalytic site by rearranging interactions between farnesyl pyrophosphate (FPP)/peptide substrate, catalytic Zn2+ ion/coordinating residues and hot-spot residues at the interface of the subunits, all of which led to the stabilization of the substrate and facilitation of the release of the product, thus collectively expediting the reaction rate. Importantly, we also identified a likely allosteric pocket on the phosphorylated FTase, which might be used for specific targeting of the enzyme. To the best of our knowledge, this is the first study that systematically examines the impact of phosphorylation on the enzymatic reaction steps, hence opens up new avenues for drug discovery studies that focus on targeting phosphorylated FTase.Öğe Protective effect of edaravone on rat testis after valproic acid treatment(Marmara University, 2022) Çelik, Çağrı; Bayrak, Bertan Boran; Hacıhasanoğlu Çakmak, Neziha; Yanardağ, RefiyeValproic acid n-dipropyl-acetic acid, VPA) is a medication used as anticonvulsant in the treatment of bipolar disorder, and for migraine prophylaxis. Long-term use of VPA is known to trigger reproductive impairment, which is mediated by elevation of testicular oxidative stress. Edaravone is used in the treatment of cerebrovascular diseases. It can diffuse into many disease-affected organs, thus shows protective effects in numerous tissues including the heart, lung, and testis. The main goal of the present study was to determine the possible protective role of edaravone against VPA-induced oxidative testicular injury. Male Sprague Dawley rats were assigned into four groups. Control rats; rats given only edaravone (30 mg/kg/day); rats given only VPA (500 mg/kg/day); rats given VPA+edaravone for seven days. Edaravone and VPA were applied intraperitoneally. After eight days, testicular tissues were taken from rats. There was a statistically significant increase in the levels of reduced glutathione, lipid peroxidation, reactive oxygen species, total oxidant status, oxidative stress index, and DNA contents as well as catalase, superoxide dismutase, glutathione-related enzymes, gamma-glutamyl transferase, acid and alkaline phosphatases, lactate dehydrogenase, myeloperoxidase and sorbitol dehydrogenase activities in VPA group. More so, advanced oxidized protein products, protein carbonyl, and nitric oxide levels were also significantly increased in VPA group. Activities of glucose-6-phosphate dehydrogenase and sodium/potassium ATPase and total antioxidant status levels remarkably decreased in VPA given group. Treatment with edaravone to VPA group significantly reverted these alterations. These findings demonstrate that administration of edaravone has a beneficial effect against testicular injury in VPA-induced oxidative stress.Öğe The effects of edaravone, a free-radical scavenger in lung injury induced by valproic acid demonstrated via different biochemical parameters(Wiley, 2021) Bayrak, Bertan Boran; Yılmaz, Sebahat; Hacıhasanoğlu Çakmak, Neziha; Yanardağ, RefiyeIn this study, we aimed to evaluate whether edaravone (EDA) has a protective role against valproic acid (VPA)-induced lung damage via its antioxidative activity. Male Sprague-Dawley rats were split into four groups. Control (n = 8) rats; rats given EDA (30 mg kg(-1) day(-1); n = 10); rats given only (VPA, 500 mg kg(-1) day(-1); n = 10); rats given VPA + EDA (in the same dose and time) for 7 days. EDA and VPA were applied intraperitoneally. After 8 days, lung tissues were immediately taken from the rats. In lung homogenates, reduced glutathione, total antioxidant status levels, and superoxide dismutase, glutathione peroxidase, sodium/potassium ATPase, paraoxonase1, and carbonic anhydrase activities significantly abated, whereas catalase, glutathione reductase, glutathione-S-transferase activities insignificantly decreased in the VPA-treated group. In contrast, lipid peroxidation, reactive oxygen species, and total oxidant status levels, glycoprotein and protein carbonyl contents, nitric oxide, hydroxyproline levels, and xanthine oxidase, lactate dehydrogenase, arginase, and prolidase activities significantly increased in the VPA-given group. Administration of EDA caused the reverse effects. As a consequence, EDA prevented oxidative stress-mediated lung injury via its robust antioxidant effects.Öğe Dimethyl sulfoxide reduces the stability but enhances catalytic activity of the main SARS-CoV-2 protease 3CLpro(John Wiley and Sons Inc, 2021) Ferreira, Juliana C.; Fadl, Samar; İlter, Metehan; Pekel, Hanife; Rezgui, Rachid; Şensoy, Özge; Rabeh, Wael M.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), one of the most challenging global pandemics of the modern era. Potential treatment strategies against COVID-19 are yet to be devised. It is crucial that antivirals that interfere with the SARS-CoV-2 life cycle be identified and developed. 3-Chymotrypsin-like protease (3CLpro) is an attractive antiviral drug target against SARS-CoV-2, and coronaviruses in general, because of its role in the processing of viral polyproteins. Inhibitors of 3CLpro activity are screened in enzyme assays before further development of the most promising leads. Dimethyl sulfoxide (DMSO) is a common additive used in such assays and enhances the solubility of assay components. However, it may also potentially affect the stability and efficiency of 3CLpro but, to date, this effect had not been analyzed in detail. Here, we investigated the effect of DMSO on 3CLpro-catalyzed reaction. While DMSO (5%-20%) decreased the optimum temperature of catalysis and thermodynamic stability of 3CLpro, it only marginally affected the kinetic stability of the enzyme. Increasing the DMSO concentration up to 20% improved the catalytic efficiency and peptide-binding affinity of 3CLpro. At such high DMSO concentration, the solubility and stability of peptide substrate were improved because of reduced aggregation. In conclusion, we recommend 20% DMSO as the minimum concentration to be used in screens of 3CLpro inhibitors as lead compounds for the development of antiviral drugs against COVID-19.Öğe Majistral ilaçlar: Olgu sunumu(Adli Tıp Kurumu, 2016) Özbek, Hanefi; Kırmızı, Neriman İpekMajistral ilaç, hasta için özel olarak hekim tarafından reçete edilen ve eczanede bu formüle göre hazırlanan ilaç olaraktanımlanmakta; majistral ilaçlarla ilgili hususlar Eczacılar ve Eczaneler Hakkında Yönetmelik hükümlerine göre değerlendirilmektedir. Majistral ilaç konusu, sık başvurulan bir ilaç reçeteleme yöntemi değildir; bu nedenle hukükî yönü ilgili kişilerce yeterince bilinmemekte veya bu hususa gereğince özen gösterilmemektedir. Bu sunumda, Adli Tıp Kurumu 5. İhtisas Kurulu'na gönderilen bir olgu üzerinden majistral ilaçlar ve bunlarla ilgili mevzuata değinilecektir.Öğe Design and synthesis of novel cylopentapyrazoles bearing 1,2,3-thiadiazole moiety as potent antifungal agents(Elsevier, 2020) Giray, Betül; Karadağ, Ayşe Esra; Şavluğ İpek, Özgecan; Pekel, Hanife; Güzel, Mustafa; Başpınar Küçük, HaticeIn drug-resistant phytopathogenic fungi, there has been extensive research on microbiological and antifungal drug development. In this study, a novel series of cylopentapyrazole bearing a 1,2,3-thiadiazole ring 2a-e were designed and synthesized according to the principle of combination of bioactive structures. Thus, we have employed a [3 + 2] cycloaddition with 4-methyl-[1,2,3] thiadiazole-5-carboxylic acid hydrazones 1a-e and cyclopentadiene ring. Novel synthesized compounds were identified with IR, 1H and 13C NMR, mass spectrometry and elemental analysis then, antifungal activities were assayed. Based on our study, a combination of the compounds 1a and 2b possess remarkable antifungal activity against Botrytis cinerea AHU 9424 with 100% inhibition. EC50 values were calculated by studying different doses in combinations with high inhibition rates. The combination of 1a + 2b has an EC50 value at 6.37 and 13.85 µg/ml concentrations against B. cinerea and F. culmorum, respectively. The combination of compound 1a + 2b, having a cylopentapyrazole ring on the 1,2,3-thiadiazole backbone, shows promising fungicidal activity and deserves further development. Additionally, the homology model of the CYP51 enzyme that belongs toFusarium moniliformewas generated using CYP51B (PDB ID: 6CR2), and molecular docking was performed using this homology model for each compound. The results of this study clearly indicate that these novel compounds can be identified as promising lead compounds and potential fungicidal agents in future.Öğe Novel synthetic approaches for bisnaphthalimidopropyl (BNIP) derivatives as potential anti-parasitic agents for the treatment of leishmaniasis(MDPI, 2019) Keskin, Elif; Üçışık, Mehmet Hikmet; Sucu, Bilgesu Onur; Güzel, MustafaLeishmaniasis is a neglected parasitic disease that is widely seen in more than 60 countries worldwide, including Turkey and its subcontinental region. There are several chemotherapy agents for the treatment of leishmaniasis, including pentavalent antimonials-i.e., sodium stibogluconate (Pentostan) and meglumine antimoniate (Glucantim), pentamidine, conventional amphotericin B deoxycholate, miltefosine, paramomycin (aminosidine), and liposomal amphotericin B. However, these therapies are usually unsatisfactory due to dose-limiting toxicity issues and limited efficacy. Furthermore, resistance gained by parasites endangers future success of these therapies. Addressing these issues, the development of novel drugs with high efficacy has a vital importance. Latest studies have shown that bisnaphthalimidopropyl (BNIP) derivatives display high activity against Leishmaniasis parasites by selectively targeting parasitic sirtuin proteins and interacting with DNA. Despite the promising anti-parasitic activity, the low solubility and toxicity on human macrophages are the limitations to overcome. This study describes the new synthesis strategies for existing-i.e., BNIPDaoct and BNIPDanon-and novel BNIP derivatives differing in respect of their alkyl linker chain lengths. The new synthesis approach provides certain advantages compared to its existing alternatives reported in the literature. The proposed methodology does not only decrease the number of synthesis steps and production time of BNIPDaoct and BNIPDanon, but also provides higher yields, thereby making the synthesis highly cost-effective.Öğe Synthesis of novel methyl jasmonate derivatives and evaluation of their biological activity in various cancer cell lines(Academic Press Inc Elsevier Science, 2019) Onur Sucu, Bilgesu; Savluğ İpek, Özgecan; Özdatlı Kurtuluş, Şükran; Yazıcı, Büşra Emine; Karakaş, Nihal; Güzel, MustafaWarburg hypothesized that the energy consumption of cancer cells is different than the normal cells. When compared to normal conditions, cancer cells do not undergo tricarboxylic acid (TCA) cycle therefore resulting in more lactate in the cells. Glycolysis pathway is a way of cancer cells to provide energy. The first step in glycolysis is the phosphorylation of glucose to glucose-6-phosphate. This reaction is catalyzed by the hexokinase-II enzyme (HK-II) which is known to be overexpressed in tumor cells. The feeding of cancer cells can be prevented by inhibiting the hexokinase-II enzyme in the first step of aerobic glycolysis. In literature, Methyl Jasmonate (MJ) is known as a Hexokinase-II inhibitor since it disposes VDAC and HK-II interaction on mitochondrial membrane. In our study, we aimed to increase the activity by synthesizing the novel MJ analogues with appropriate modifications. Here we report Hexokinase-2 enzyme and cell viability study results in different cancer cells. Based on the three different cancer cell lines we investigated, our novel MJ analogues proved to be more potent than the original molecule. Thus this research may provide more efficacious/ novel HK-II inhibitors and may shed light to develop new anti-cancer agents.Öğe Evaluation of the antidiabetic activity of Alchemilla persica Rothm. In mice with diabetes induced by alloxan(Turkish Pharmacists Association, 2019) Özbilgin, Serkan; Özbek, Hanefi; Kırmızı, Neriman İpek; Ergene Öz, Burçin; Kurtul, Ekin; Özrenk, Bade Cevriye; Saltan İşcan, Gülçin; Bahadır Acıkara, ÖzlemObjectives: Alchemilla species are used in Turkish folk medicine for the treatment of many diseases together with diabetes. Alchemilla persica, belonging to this genus, is widely distributed in Eastern Anatolia as well as in Caucasia, northern and northeastern Iran, and northern Iraq. Materials and Methods: Methanolic-water extracts of the aerial parts and roots of A. persica were evaluated for their hypoglycemic activities in mice with alloxan-induced diabetes in order to verify its usage in folk medicine. Results: None of the tested extracts exhibited a significant lowering effect on blood glucose levels. However, the aerial parts notably increased blood glucose levels at doses of 100 mg/kg and 200 mg/kg. Conclusion: A. persica usage as an antidiabetic is not confirmed in the present study.Öğe Hepatoprotective effects of coriandrum sativum essential oil against acute hepatotoxicity induced by carbon tetrachloride on rats(University of Istanbul, 2016) Özbek, Hanefi; Kırmızı, Neriman İpek; Cengiz, Nureddin; Erdoğan, EnderThe aim of this study was to evaluate effect of Coriandrum sativum (CS) essential oil in rat model of carbon tetrachloride (CCl4) induced liver toxicity. Experimental groups were formed as follows: isotonic saline solution (ISS), silibinin, CS-1 (0,3ml/ kg), CS-2 (0,6 ml/kg). Agents were administered intraperitoneally. Blood and liver tissues were collected at the end of the study ended. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured. Liver tissues were evaluated histopathologically. One-way analysis of variance (ANOVA) was used for statistical analyses.As a result silibinin and CS-2 decreased blood AST and ALT levels of their groups and these biochemical results were supported by histopathological results. In conclusion this study has provided evidence that Coriandrum sativum essential oil has significant hepatoprotective effect on carbon tetrachloride induced liver toxicity in rats.
