Yazar "Tokay, Esra" seçeneğine göre listele

Listeleniyor 1 - 8 / 8
  • [ X ]
    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, Mehmet
    Background: 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 therapy
  • [ X ]
    Öğe
    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.
  • [ X ]
    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, 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.
  • Küçük Resim
    Öğe
    Prodrugs for Nitroreductase Based Cancer Therapy-5: Development of Trinitroaniline Prodrugs/Ssap-NtrB Combinations for Liver Cancer Using Intracellular and Extracellular Conditions
    (John Wiley and Sons Inc, 2021) Hacıoğlu, Nelin; Güngör, Tuğba; Tokay, Esra; Ay, Mehmet
    In this study, a series of trinitroaniline derivatives (TNA1-8) were synthesized and investigated as potential antitumor agents for enzyme-prodrug therapy. Enzymatic efficiency of Ssap-NtrB on prodrug candidates was determined with HPLC analysis and kinetic studies. The anti-proliferative properties of compounds were determined against four cancer cell lines (Hep3B, PC3, HT-29, and Saos-2) and a healthy cell line (HUVEC) via MTT assay. Intracellular and extracellular prodrug-enzyme treatments were carried out on Hep3B cells. Herewith, the expression of the Ssap-NtrB gene was confirmed with this study. IC50 values of piperidine and 1,3-cyclohexyl derivatives (TNA4 and TNA7) were identified as 1.724 nM and 1.640 nM at extracellular conditions. In intracellular conditions, it was determined as 0.293 μM and 0.393 μM, respectively. In summary, 2,4,6-trinitroaniline derivatives, especially compounds TNA4 and TNA7 might be used as prodrug candidates along with Ssap-NtrB for hepatocellular carcinoma therapy and the development of new prodrugs at cancer treatments.
  • [ X ]
    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, 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.
  • [ X ]
    Öğe
    Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses
    (Amer Chemical Soc, 2024) Donmez, Serhat; Lapinskaite, Ringaile; Atalay, Hazal Nazlican; Tokay, Esra; Kockar, Feray; Rycek, Lukas; Ozbil, Mehmet
    The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound's strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.
  • [ X ]
    Öğe
    Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma
    (Amer Chemical Soc, 2022) Antika, Gizem; Cinar, Zeynep Ozlem; Secen, Esma; Ozbil, Mehmet; Tokay, Esra; Kockar, Feray; Prandi, Cristina
    Strigolactones (SLs), carotenoid-derived phytohormones, control the plant response and signaling pathways for stressful conditions. In addition, they impact numerous cellular processes in mammalians and present new scaffolds for various biomedical applications. Recent studies demonstrated that SLs possess potent antitumor activity against several cancer cells. Herein, we sought to elucidate the inhibitory effects of SL analogs on the growth and survival of human brain tumor cell lines. Among four tested SLs, we showed for the first time that two lead bioactiphores, indanone-derived SL and EGO10, can inhibit cancer cell proliferation, induce apoptosis, and induce G1 cell cycle arrest at low concentrations. SL analogs were marked by increased expression of Bax/Caspase-3 genes and downregulation of Bcl-2. In silico studies were conducted to identify drug-likeness, blood-brain barrier penetrating properties, and molecular docking with Bcl-2 protein. Taken together, this study indicates that SLs may be promising antiglioma agents, presenting novel pharmacophores for further preclinical and clinical assessment.
  • [ X ]
    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, 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.