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Öğe Antiproliferative activity of Humulus lupulus extracts on human hepatoma (Hep3B), colon (HT-29) cancer cells and proteases, tyrosinase, ?-lactamase enzyme inhibition studies(Taylor & Francis Ltd, 2016) Onder, Ferah Comert; Ay, Mehmet; Turkoglu, Sumeyye Aydogan; Kockar, Feray Tura; Celik, AyhanThe aims of this study were to examine the antiproliferation of Humulus lupulus extracts on human hepatoma carcinoma (Hep3B) and human colon carcinoma (HT-29) cell lines along with enzyme inhibitory effects of the crude extracts. Potential cell cytotoxicity of six different H. lupulus extracts were assayed on various cancer cells using MTT assay at 24, 48 and 72h intervals. Methanol-1 extract has inhibited the cell proliferation with doses of 0.6-1mg/mL in a time dependent (48 and 72 hours) manner in Hep3B cells with 70% inhibition, while inhibitory effect was not seen in colon cancer cells. Acetone extract has increased the cell proliferation at low doses of 0.1mg/mL for 72h in Hep3B cells and 0.1-0.2mg/mL for 48 and 72h in HT29 cells. The inhibitory effects of the extracts were compared by relative maximum activity values (V-max) using proteases such as -chymotrypsin, trypsin and papain, tyrosinase and -lactamase (penicillinase).Öğe Assessment of release and anticancer effect of innovative pH-responsive and antioxidant-biodegradable hydrogel by using Parthenocissus quinquefolia L. extract as a crosslinker(Elsevier, 2023) Onder, Ferah Comert; Kalin, Sevil; Onder, Alper; Ozay, Hava; Özay, ÖzgürThe level of toxicity in cancer treatment with chemotherapy can negatively affect the treatment process. Therefore, targeted drug delivery systems play an important role in reducing treatment-related toxicities. Hydrogels with three-dimensional networks are being investigated as drug delivery systems due to their unique properties such as swelling capacity, biocompatibility, and bioavailability. Poly(2-hydroxyethyl methacrylate-co- methacrylic acid)/PQ (p(HEMA-co-MAA)/PQ) hydrogel was prepared by redox polymerization method using Parthenocissus quinquefolia L. (PQ) plant extract, known for its anticancer, antioxidant, and antimicrobial properties, as a crosslinker. PQ hydrogels were prepared with various monomer and cross-linker ratios. The p(HEMAco-MAA)/PQ10 (1:1) with a highly porous structure exhibited high swelling behavior. The phenolic content of p (HEMA-co-MAA)/PQ10 (1:1) hydrogel which has been determined to have high in vitro biodegradability at pH 6.5, increased with the amount of PQ extract used as crosslinker. The pH-responsive, antioxidant, biodegradable, and highly porous p(HEMA-co-MAA)/PQ10 (1:1) hydrogel showed higher doxorubicin (Dox) release behavior at pH 6.5. The Dox-loaded p(HEMA-co-MAA)/PQ10 (1:1) hydrogel drug carrier showed its anticancer effect on inhibition of colonies and cell proliferation against breast cancer cell lines. Our findings show that the p(HEMAco-MAA)/PQ10 (1:1) hydrogel using the PQ plant extract as a crosslinker will be significant potential in combination and cancer therapy studies.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 Comparative Study of Antioxidant Properties and Total Phenolic Content of the Extracts of Humulus lupulus L. and Quantification of Bioactive Components by LC-MS/MS and GC-MS(Amer Chemical Soc, 2013) Onder, Ferah Comert; Ay, Mehmet; Sarker, Satyajit D.In this research, antioxidant activities of various extracts obtained from Humulus lupulus L. were compared by DPPH, ABTS, FRAP, and CUPRAC assays. The amount of total phenolic components determined by the Folin-Ciocalteu reagent was found to be highest for 25% aqueous ethanol (9079 +/- 187.83 mg Ferulic acid equivalent/100 g extract) and methanol-1 (directly) (8343 +/- 158.39 mg Ferulic acid equivalent/100 g extract) extracts. The n-hexane extract of H. lupulus exhibited the greatest with DPPH (14.95 +/- 0.03 mu g Trolox equivalent/g sample). The highest phenolic content in the ethanolic extract could be the major contributor to its highest CUPRAC activity (3.15 +/- 0.44 mmol Trolox equivalent/g sample). Methanol-2 (n-hexane, acetone, and methanol) and methanol-3 (n-hexane, dichloromethane, ethylacetate, and methanol) extracts, respectively, exhibited the most potent ABTS (7.35 +/- 0.03 mM Trolox equivalent) and FRAP (1.56 +/- 0.35 mmol Fe2+/g sample) activities. Some of the components from the crude extracts were determined by LC-MS/MS and GC-MS analyses. Comparative screening of antioxidant activities of H. lupulus extracts and quantification of some major components by LC-MS/MS, qualitatively analysis of the reported ones which were optimal under negative ion SIM mode and coinjection, are going to be valuable for food and health applications.Öğe Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors(Amer Chemical Soc, 2020) Onder, Ferah Comert; Durdagi, Serdar; Sahin, Kader; Ozpolat, Bulent; Ay, MehmetEukaryotic elongation factor-2 kinase (eEF-2K) is an unusual alpha kinase commonly upregulated in various human cancers, including breast, pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K is relevant to poor prognosis and shorter patient survival in breast and lung cancers and validated it as a molecular target using genetic methods in related in vivo tumor models. Although several eEF-2K inhibitors have been published, none of them have shown to be potent and specific enough for translation into clinical trials. Therefore, development of highly effective novel inhibitors targeting eEF-2K is needed for clinical applications. However, currently, the crystal structure of eEF-2K is not known, limiting the efforts for designing novel inhibitor compounds. Therefore, using homology modeling of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides including compounds A1, A2, and B1-B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast cancer cells. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1-B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 mu M concentrations compared to compounds B1-B4, supporting the in silico findings. In conclusion, the results of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic applications.Öğe Humidity effect on real-time response of tetranitro-oxacalix[4] arene-based surface plasmon resonance (SPR) acetone sensor at room temperature(Elsevier Gmbh, 2023) Sen, Sibel; Onder, Ferah Comert; Capan, Rifat; Ay, Mehmet; Erdogan, Cansu OzkayaWe report the effect of humidity on the acetone sensitivity of nano-sized thin films obtained by spin coating the oxacalix[4]arenes(1,3) molecules on suitable substrates in this work. The surface morphologies and volatile organic compound (VOC) sensor properties of spin-coated thin films were examined using atomic force microscopy (AFM) and surface plasmon resonance (SPR), respectively. It was determined that the sensitivities calculated from the measurements performed using a mixture of acetone and water vapor were 14% and 11% incorrect for the 1 and 3 thin film sensors, respectively, compared to those performed with dry air and acetone mixture.Öğe Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies(Elsevier Science Inc, 2022) Onder, Ferah Comert; Sahin, Kader; Senturk, Murat; Durdagi, Serdar; Ay, MehmetInhibition of high cholinesterase levels including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), is one of the most important strategies for the treatment of Alzheimer's disease (AD). Clinically limited drugs are used in the treatment of AD, so there is a need to find new effective inhibitors today. Therefore, in this study, synthesized six coumarin carboxamides (A1, A2, B1-B4) were evaluated against AChE and BChE by combined in silico and in vitro studies. The in vitro assessment of studied compounds revealed that A1, A2, B3, and B4 showed highest inhibition potential against AChE and BChE. As demonstrated with our structure activity relationship (SAR) study, the promising inhibition result of AChE at nanomolar concentrations was obtained with heterocyclic amines including pyrrolidine and N-methyl piperazine moieties for tertiary amide substituted coumarin compounds B3 and B4, displaying K-1 values of 9.78 nM and 8.07 nM, respectively. Thus, compounds B3 and B4 had around 5.7- and 6.9-fold more potency compared to the reference molecule, neostigmine. Moreover, coumarin-3-carboxamide derivative A1 bearing benzylmorpholine moiety on coumarin scaffold at position 3 displayed stronger inhibition potential against BChE. Furthermore, in order to better understand their molecular mechanisms in these targets, we conducted molecular docking and MD simulations. Our promising preclinical results show that the lead compounds A1, A2, B3 and B4 have high potential as effective inhibitors for the treatment of AD.Öğe In vitro and in silico studies of nitrobenzamide derivatives as potential anti-neuroinflammatory agents(Taylor & Francis Inc, 2020) Kulabas, Seda Savranoglu; Onder, Ferah Comert; Yilmaz, Yakup Berkay; Ozleyen, Adem; Durdagi, Serdar; Sahin, Kader; Ay, MehmetCommunicated by Ramaswamy H. SarmaÖğe New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor(Amer Assoc Cancer Research, 2019) Onder, Ferah Comert; Ay, Mehmet; Durdagi, Serdar; Ozpolat, Bulent; Kantarcioglu, Isik[Anstract Not Available]Öğe Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy(Royal Soc Chemistry, 2022) Onder, Ferah Comert; Siyah, Pinar; Durdagi, Serdar; Ay, Mehmet; Ozpolat, BulentEukaryotic elongation factor 2 kinase (eEF2K) has been shown to be an important molecular driver of tumorigenesis and validated as a potential novel molecular target in various solid cancers including triple negative breast cancer (TNBC). Therefore, there has been significant interest in identifying novel inhibitors of eEF2K for the development of targeted therapeutics and clinical translation. Herein, we investigated the effects of indole ring containing derivatives of etodolac, a nonsteroidal anti-inflammatory (NSAID) drug, as potential eEF2K inhibitors and we designed and synthesized seven novel compounds with a pyrano[3,4-b] indole core structure. We evaluated the eEF2K inhibitory activity of seven of these novel compounds using in silico molecular modeling and in vitro studies in TNBC cell lines. We identified two novel compounds (EC1 and EC7) with significant in vitro activity in inhibiting eEF2K in TNBC cells. In conclusion, our studies indicate that pyrano[3,4-b] indole scaffold containing compounds demonstrate marked eEF2K inhibitory activity and they may be used as eEF2K inhibitors for the development of eEF2K-targeted therapeutics.Öğe Preparation of antioxidant-biodegradable poly(acrylic acid-co-2-hydroxyethyl methacrylate) hydrogel using rutin as a crosslinker: Drug release and anticancer activity(Elsevier, 2023) Onder, Ferah Comert; Onder, Alper; Ilgin, Pinar; Ozay, Hava; Özay, ÖzgürIt is important to develop drug-release systems that reduce the side effects of chemotherapy drugs, can regulate drug release, and can be designed for a target to keep the quality of life of cancer patients high. In this study, a polyphenol compound rutin was used as a natural crosslinker to prepare poly(acrylic acid-co-2-hydroxyethyl methacrylate)/rutin (RTN hydrogel) as a drug carrier. The swelling behavior, thermal stability, in vitro biode-gradability, and antioxidant activity of this hydrogel were determined. The prepared hydrogel had in vitro biodegradability and antioxidant properties. The maximum doxorubicin (DOX) amount adsorbed by the RTN hydrogel was 32.96 & PLUSMN; 1.83 mg/g. The DOX-loaded RTN hydrogel displayed drug release behavior in normal and cancer cell media. At the same time, the effect of the DOX-loaded hydrogel on triple negative breast cancer (TNBC) cell lines was investigated. Our results show that the RTN hydrogel, prepared using the natural product of rutin as a crosslinker with in vitro biodegradability and antioxidant properties, offers great promise as a high-impact carrier in the drug distribution system.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, 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 Self-assembled silibinin-containing phosphazene/cystamine hybrid nanospheres as biodagradable dual-drug carriers with improved anticancer activity on a breast cancer cell line(Elsevier, 2023) Ozsoy, Fatma; Onder, Ferah Comert; Ilgin, Pinar; Ozay, Hava; Onder, Alper; Özay, ÖzgürIn this study, pH and redox sensitive biodegradable PPZs@Silibinin polymeric nanospheres were synthesized by the polymerization reaction of Hexachlorocyclotriphosphazene (HCCP), Cystamine dihydrochloride (CA) and the anticancer drug Silibinin as monomers. Later designed as a therapeutic system, this nano drug-carrier was also loaded with Doxorubicin (Dox), a type of cancer drug. As a result, a drug self-delivery system (DSDS) was developed, which had the property of biodegradation in tumor tissues thanks to the redox active disulfide bonds in its structure from pH-sensitive nanospheres containing two anticancer drugs. Biodegradation-associated in vitro release of cancer drug (Dox) from the Dox loaded PPZs@Silibinin nano drug-carrier was performed in the presence of glutathione (GSH) at pH 6.5 and pH 7.4. While 93.06% Dox release was observed in pH 6.5 medium containing 10 mM GSH in 24 h, this value was 56.60% in pH 7.4 + 10 mM GSH medium. In addition, clonogenic analysis and cytotoxicity studies were performed on the MDA-MB-231 cell line to determine the anticancer properties of PPZs@Silibinin loaded with Dox. It was determined that PPZs@Silibinin@Dox nanospheres containing 20.5 nM Dox for 0.75 mu L are highly effective in MDA-MB-231 cells than free Dox.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.
