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Öğe Biological evaluation and molecular docking. studies of nitro benzamide derivatives with respect to in vitro anti-inflammatory activity(Elsevier, 2017) Turner, Tugba B.; Onder, Ferah Comert; Ipek, Hande; Gungor, Tugba; Savranoglu, Seda; Tok, Tugba Taskin; Celik, AyhanA series of nitro substituted benzamide derivatives were synthesized and evaluated for their potential anti-inflammatory activities in vitro. Firstly, all compounds (1-6) were screened for their inhibitory capacity on LPS induced nitric oxide (NO) production in RAW264.7 macrophages. Compounds 5 and 6 demonstrated significantly high inhibition capacities in a dose-dependent manner with IC50 values of 3.7 and 53 mu M, respectively. These two compounds were also accompanied by no cytotoxicity at the studied concentrations (max 50 mu M) in macrophages. Molecular docking analysis on iNOS revealed that compounds 5 and 6 bind to the enzyme more efficiently compared to other compounds due to having optimum number of nitro groups, orientations and polarizabilities. In addition, 5 and 6 demonstrated distinct regulatory mechanisms for the expression of the iNOS enzyme at the mRNA and protein levels. Specifically, both suppressed expressions of COX-2, IL-1 beta and TNF-alpha significantly, at 10 and 20 mu M. However, only compound 6 significantly and considerably decreased LPS-induced secretion of IL-1 beta and TNF-alpha. These results suggest that compound 6 may be a multi-potent promising lead compound for further optimization in structure and as well as for in vivo validation studies. (C) 2016 Published by Elsevier B.V.Öğe Carbon nanofiber/poly(tetrahydro[1,4] dioxino[2,3-b] thieno[3,4-e][1,4] dioxine) binder-free composite redox-active electrode for electrochemical energy storage applications(Royal Soc Chemistry, 2017) Yigit, Deniz; Soysal, Furkan; Gungor, Tugba; Cicek, Burhanettin; Gullu, MustafaWe report the preparation and supercapacitive properties of a novel composite electrode material based on carbon nanofiber (CNF) and poly(tetrahydro[1,4] dioxino[2,3-b] thieno[3,4-e][1,4] dioxine) (PTDTD) for electrochemical energy storage applications. The CNF/PTDTD composite electrode was directly prepared by electrodeposition of PTDTD on the CNF coated substrate without any binder or conductive additives. The symmetric solid-state supercapacitor device was assembled by using these CNF/PTDTD composite electrodes. In addition, CNF/CNF and CNF/poly(3,4-ethylenedioxythiophene) (PEDOT) symmetric supercapacitor devices were also fabricated to make a detailed performance comparison. The electrochemical characteristics of all supercapacitor devices were comprehensively evaluated by CV, GCD and EIS measurements. The CNF/PTDTD composite electrodes delivered a maximum specific capacitance of 332 F g(-1), energy density of 166 W h k g(-1), power density of 4.9 kW kg(-1) and an excellent cycling stability with 89% capacitance retention after 12 500 cycles at 2 mA cm(-2) current density while CNF/PEDOT electrodes were able to reach a specific capacitance of 254 F g(-1), energy density of 128.8 W h kg(-1) and power density of 5.45 kW kg(-1) in those supercapacitor devices. These results confirmed that PTDTD has significant potential to be a good alternative redox-active material and CNF/PTDTD composite structure is a promising candidate for supercapacitor applications.Öğe Electrochemical behavior and voltammetric determination of some nitro-substituted benzamide compounds(Tubitak Scientific & Technological Research Council Turkey, 2018) Saglam, Ozlem; Comert Onder, Ferah; Gungor, Tugba; Ay, Mehmet; Dilgin, YusufVoltammetric behaviors of six nitro-substituted benzamides, which are potential prodrug candidates for nitroreductase-based cancer therapy, were investigated using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The electrochemical behavior of aromatic nitro (ArNO2) compounds by CV indicates that compounds involve various reduction/oxidation steps including the formation of aromatic nitro radical, nitroso, hydroxylamine, and amine groups. Applicability of the voltammetric determination of these prodrug candidates was studied by recording their DPVs, carried out in mixed media (Britton Robinson buffer solution + DMF) at various pH values on a pencil graphite electrode (PGE). Results show that the PGE can offer a disposable, low-cost, and sensitive electrochemical determination method for identifying nitro benzamide compounds. Under the experimental conditions, the PGE had a linear response range from 0.5 to 100 mu M 4-nitro- N-(2-nitrophenyl)benzamide (compound 2). This voltammetric procedure indicates that nitro-substituted benzamide drugs can be successfully determined in pharmaceutical samples.Öğe Modification of existing antibiotics in the form of precursor prodrugs that can be subsequently activated by nitroreductases of the target pathogen(Pergamon-Elsevier Science Ltd, 2016) Celik, Ayhan; Yetis, Gulden; Ay, Mehmet; Gungor, TugbaThe use of existing antibiotics in the form of prodrug followed by activation using enzymes of pathogenic origin could be a useful approach for antimicrobial therapy. To investigate this idea, a common antibiotic, sulfamethoxazole has been redesigned in the form of a prodrug by simple functional group replacement. Upon reductive activation by a type I nitroreductase from a pathogen, the drug displayed enhanced antimicrobial capacity. This strategy could improve the efficacy and selectively of antibiotics and reduce the incidence of resistance. (C) 2016 Elsevier Ltd. All rights reserved.Öğe One pot, multicomponent protocol for the synthesis of novel imidazo[1,2-a]pyrimidine-based pyran analogs: a potential biological scaffold(Springer Wien, 2020) Gungor, TugbaAn efficient procedure between imidazo[1,2-a]pyrimidine-2-carbaldehyde, malononitrile, enolizable C-H activated acidic compounds, and sodium carbonate is described for the synthesis of potential biologically active, novel imidazo[1,2-a]pyrimidine-based pyran analogs through one pot, multicomponent reactions at room temperature. This method provided mild reaction conditions, simple purification without column chromatography, and moderate to good yields for the construction of imidazo[1,2-a]pyrimidine-based pyran derivatives. The structures of target compounds were established with different spectroscopic analyses. [GRAPHICS] .Öğe Poly(thieno[3,4-b][1,4] dioxine) and poly([1,4] dioxino[2,3-c] pyrrole) derivatives: p-and n-dopable redox-active electrode materials for solid state supercapacitor applications(Elsevier, 2013) Yigit, Deniz; Gungor, Tugba; Gullu, MustafaWe report the synthesis and supercapacitive properties of novel poly(2,3,4a, 9a-tetrahydro[ 1,4] dioxino[2,3-b] thieno[3,4-e][1,4] dioxine) (pTDTD) and poly(7-butyl-3,4a, 7,9a-tetrahydro- 2H-[1,4] dioxino[2',3': 5,6][1,4] dioxino[2,3-c] pyrrole) (pTDDP) as redox-active electrode materials for supercapacitor applications. At first, new thiophene and pyrrole monomers containing of fused two 1,4-dioxane rings were successfully synthesized and their conducting polymers were prepared electrochemically on a stainless steel (SS) electrode. Symmetric and asymmetric solid state pseudocapacitor devices were fabricated in order to evaluate supercapacitive performances of newly designed pTDTD and pTDDP. The SS electrodes modified with pTDTD and pTDDP were used as an anode material against pEDOT coated SS cathode in asymmetric devices and as both anode and cathode material in symmetric devices. Capacitive behaviors and performances of the devices were tested by cyclic voltammetry (CV), galvanostatic charge/discharge (GCD) and electrochemical impedance spectroscopy (EIS) techniques. In symmetric devices, pTDTD provided a specific capacitance of 260 F/g and specific energy of 288Wh/kg, while the pTDDP was found to be not a suitable redox-active electrode material for pseudocapacitor applications. (C) 2013 Elsevier B.V. All rights reserved.Öğe Prodrugs for Nitroreductase Based Cancer Therapy-1: Metabolite Profile, Cell Cytotoxicity and Molecular Modeling Interactions of Nitro Benzamides with Ssap-NtrB(Bentham Science Publ Ltd, 2018) Gungor, Tugba; Yetis, Gulden; Onder, Ferah C.; Tokay, Esra; Tok, Tugba T.; Celik, Ayhan; Ay, MehmetBackground: Directed Enzyme Prodrug Therapy (DEPT) as an alternative method against conventional cancer treatments, in which the non-toxic prodrug is converted to highly cytotoxic derivative, has attracted an ample attentions in recent years for cancer therapy studies. Objective: The metabolite profile, cell cytotoxicity and molecular modeling interactions of a series of nitro benzamides with Ssap-NtrB were investigated in this study. Method: A series of nitro-substituted benzamide prodrugs (1-4) were synthesized and firstly investigated their enzymatic reduction by Ssap-NtrB (S. saprophyticus Nitroreductase B) using HPLC analysis. Resulting metabolites were analyzed by LC-MS/MS. Molecular docking studies were performed with the aim of the investigating the relationship between nitro benzamide structures (prodrugs 1-4) and Ssap-NtrB at molecular level. Cell viability assay on two cancer cell lines, hepatoma (Hep3B) and colon (HT-29) cancer models and healthy cell model HUVEC. Upon the reduction of benzamide prodrugs by Ssap-NtrB, the corresponding amine effectors were tested in a cell line panel comprising PC-3, Hep3B and HUVEC cells and were compared with the established NTR substrates, CB1954 (an aziridinyl dinitrobenzamide). Results: Cell viability assay resulted in while prodrugs 1, 2 and 3 had no remarkable cytotoxic effects, prodrug 4 showed the differential effect, showing moderate cytotoxicity with Hep3B and HUVEC. The metabolites that obtained from the reduction of nitro benzamide prodrugs (1-4) by Ssap-NtrB, showed differential cytotoxic effects, with none toxic for HUVEC cells, moderate toxic for Hep3B cells, but highly toxic for PC3 cells. Conclusion: Amongst all metabolites of prodrugs after Ssap-NtrB reduction, N-(2,4-dinitrophenyl)-4-nitrobenzamide (3) was efficient and toxic in PC3 cells as comparable as CB1954. Kinetic parameters, molecular docking and HPLC results also confirm that prodrug 3 is better for Ssap-NtrB than 1, 2 and 4 or known cancer prodrugs of CB1954 and SN23862, demonstrating that prodrug 3 is an efficient candidate for NTR based cancer therapyÖğe PRODRUGS FOR NITROREDUCTASE BASED CANCER THERAPY-2: Novel amide/Ntr combinations targeting PC3 cancer cells(Elsevier France-Editions Scientifiques Medicales Elsevier, 2019) Gungor, Tugba; Onder, Ferah Comert; Tokay, Esra; Gulhan, Unzile Guven; Hacioglu, Nelin; Tok, Tugba Taskin; Celik, AyhanThe use of nitroreductases (NTR) that catalyze the reduction of nitro compounds by using NAD(P)H in GDEPT (Gene-directed enzyme prodrug therapy) studies which minimize toxicity at healthy cells and increases concentration of drugs at cancer cells is remarkable. Discovery of new prodrugiNTR combinations is necessary to be an alternative to known prodrug candidates such as CB1954, SN23862, PR 104A. For this aim, nitro containing aromatic amides (A1-A23)(2) were designed, synthesized, performed in silico ADMET and molecular docking techniques in this study. Prodrug candidates were studied on reduction potentials with Ssap-NtrB by HPLC system. Also, cyototoxic properties and prodrug ability of these amides were investigated using different cancer cell lines such as Hep3B and PC3. As a result of theoretical and biological studies, combinations of A5, A6 and A20 with Ssap-NtrB can be suggested as potential prodrugs/enzyme combinations at NTR based cancer therapy compared with CB1954/NfsB. (C) 2019 Elsevier Masson SAS. All rights reserved.Öğe Prodrugs for nitroreductase based cancer therapy-4: Towards prostate cancer targeting: Synthesis of N-heterocyclic nitro prodrugs, Ssap-NtrB enzymatic activation and anticancer evaluation(Academic Press Inc Elsevier Science, 2020) Gungor, Tugba; Tokay, Esra; Gulhan, Unzile Guven; Hacioglu, Nelin; Celik, Ayhan; Kockar, Feray; Ay, MehmetIn this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, H-1 NMR, C-13 NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell. It was observed that synthesized compounds NHN1-16 exhibited different cytotoxic profiles. Pyrimidine derivative NHN3 and triazine derivative NHN5 can be good drug candidates for prostate cancer with IC50 values of 54.75 mu M and 48.9 mu M, respectively. Compounds NHN6, NHN10, NHN12, NHN14 and NHN16 were selected as prodrug candidates because of non-toxic properties against three different cell models. The NHN prodrugs and Ssap-NtrB combinations were applied to SRB assay to reveal the prodrug capabilities of these selected compounds. SRB screening results showed that the metabolites of all selected non-toxic compounds showed remarkable cytotoxicity with IC50 values in the range of 1.71-4.72 nM on prostate cancer. Among the tested compounds, especially piperazine derivatives NHN12 and NHN14 showed significant toxic effect with IC50 values of 1.75 nM and 1.79 nM against PC3 cell compared with standart prodrug CB1954 (IC50: 1.71 nM). Novel compounds NHN12 and NHN14 can be considered as promising prodrug candidates for nitroreductase-prodrug based prostate cancer therapy.Öğe Prodrugs for nitroreductase-based cancer therapy-3: Antitumor activity of the novel dinitroaniline prodrugs/Ssap-NtrB enzyme suicide gene system: Synthesis, in vitro and in silico evaluation in prostate cancer(Elsevier France-Editions Scientifiques Medicales Elsevier, 2020) Tokay, Esra; Gungor, Tugba; Hacioglu, Nelin; Onder, Ferah Cornett; Gullhan, Unzile Guven; Tok, Tugba Taskin; Celik, AyhanProdrugs for targeted tumor therapies have been extensively studied in recent years due to not only maximising therapeutic effects on tumor cells but also reducing or eliminating serious side effects on healthy cells. This strategy uses prodrugs which are safe for normal cells and form toxic metabolites (drugs) after selective reduction by enzymes in tumor tissues. In this study, prodrug candidates (1-36) containing nitro were designed, synthesized and characterized within the scope of chemical experiments. Drug-likeness properties of prodrug candidates were analyzed using DS 2018 to investigate undesired toxicity effects. In vitro cytotoxic effects of prodrug canditates were performed with MTT assay for human hepatoma cells (Hep3B) and prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) as healthy control. Non-toxic compounds (3, 5, 7,10, 12, 15,17, 19 and 21-23), and also compounds (1, 2, 5, 6, 9, 11, 14, 16, 20 and 24) which had low toxic effects, were selected to examine their suitability as prodrug canditates. The reduction profiles and kinetic studies of prodrug/Ssap-NtrB combinations were performed with biochemical analyses. Then, selected prodrug/Ssap-NtrB combinations were applied to prostate cancer cells to determine toxicity. The results of theoretical, in vitro cytotoxic and biochemical studies suggest 14/Ssap-NtrB, 22/Ssap-NtrB and 24/Ssap-NtrB may be potential prodrug/enzyme combinations for nitroreductase (Ntr)-based prostate cancer therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.Öğe Synthesis and biological evaluation of 2,4,6-trinitroaniline derivatives as potent antitumor agents(Springer Wien, 2020) Hacioglu, Nelin; Gungor, Tugba; Tokay, Esra; Onder, Ferah Comert; Ay, Mehmet; Kockar, FerayNitro group-containing compounds are well known as effective anticancer drugs. The aim of the study is to synthesize a series of trinitroaniline derivatives to determine their potential antitumor activities on diverse cancer cell models, anti-apoptotic and anti-metastatic features on hepatoma cells. The anti-proliferative studies show that IC(50)values ofN-phenyl-2,4,6-trinitroaniline,N-(2,4,6-trinitrophenyl)naphthalen-1-amine,N-(2,4,6-trinitrophenyl)naphthalen-2-amine,N-(3-nitrophenyl)-2,4,6-trinitroaniline were similar to IC(50)value of cisplatin in Hep3B cells. In fact, IC(50)value ofN-(3,5-difluorophenyl)-2,4,6-trinitroaniline is better than cisplatin. In addition, all compounds could decrease the expression of the cell cycle checkpoint protein cyclin D1. To investigate the effect of compounds on the apoptotic pathway, mRNA and protein expressions of Bcl-2 and Bax were analyzed with qRT-PCR and Western blot. Annexin V staining assay, apoptotic mRNA and protein analysis indicate thatN-isopropyl-2,4,6-trinitroaniline,N-(2,4,6-trinitrophenyl)-5-methylisoxazole-3-amine,N-(3-nitrophenyl)-2,4,6-trinitroaniline,N-(4-nitrophenyl)-2,4,6-trinitroaniline induce intrinsic apoptosis by increasing the ratio of Bax/Bcl-2 expression. In addition, colony formation and wound healing assays confirmed that these compounds also inhibit the metastatic activity of Hep3B cells. 2,4,6-Trinitroaniline derivatives, especiallyN-(3-nitrophenyl)-2,4,6-trinitroaniline might be used as candidate for the development of new antitumor drugs.Öğe Synthesis of new imine-/amine-bearing imidazo[1,2-a]pyrimidine derivatives and screening of their cytotoxic activity(Tubitak Scientific & Technological Research Council Turkey, 2023) Gungor, Tugba; Atalay, Hazal Nazlican; Yilmaz, Yakup Berkay; Tumer, Tugba Boyunegmez; Ay, MehmetImidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR,1H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 mu M and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 mu M, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment.Öğe Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles(Royal Soc Chemistry, 2024) Yilmaz, Yakup Berkay; Gungor, Tugba; Donmez, Serhat; Atalay, Hazal Nazlican; Siyah, Pinar; Durdagi, Serdar; Ay, MehmetThe development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.
