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    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, Ayhan
    The 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.
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    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, Mehmet
    In 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.
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    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, Ayhan
    Prodrugs 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.
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    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, Feray
    Nitro 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.