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    Delivery of Small Molecule EF2 Kinase Inhibitor for Breast and Pancreatic Cancer Cells Using Hyaluronic Acid Based Nanogels
    (Springer/Plenum Publishers, 2020) Cömert Önder, Ferah; Sağbaş Suner, Selin; Şahiner, Nurettin; Ay, Mehmet; Özpolat, Bülent
    Purpose To evalauted natural polymeric biomaterials including hyaluronic acid (HA) and its copolymeric form HA:Suc nanoparticles (NPs) as drug carrier systems for delivery of hydrophobic small molecule kinase EF2-kinase inhibitor in breast and pancreatic cancer cells. Methods In vitro cellular uptake studies of Rhodamine 6G labaled HA:Suc nanoparticles were evaluated by using flow cytometry analysis and fluorescent microscopy in breast (MDA-MB-231 and MDA-MB-436) and pancreatic cancer cells (PANC-1 and MiaPaca-2). Besides, in vitro release study of compound A (an EF2-kinase inhibitor) as a model hydrophobic drug was performed in the cancer cells. Results These biological evaluation studies indicated that HA and HA:Suc NPs provided a highly effective delivery of compound A were into breast and pancreatic cancer cells, leading to significant inhibition of cell proliferation and colony formation of breast and pancreatic cancer cells. Conclusion HA-sucrose NPs incorporating an EF2-Kinase inhibitor demonstrate significant biologic activity in breast and pancreatic cancer cells. This is the first study that shows natural polymeric drug carriers succesfully deliver a hydrofobic cancer drug into cancer cells. Nanoparticles based on HA:Suc are effective in delivering hydrofobic cancer drugs in breast and pancreatic cancers.
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    Hyaluronic acid and hyaluronic acid: Sucrose nanogels for hydrophobic cancer drug delivery
    (Elsevier Science Bv, 2019) Sağbaş Suner, Selin; Ari, Betül; Cömert Önder, Ferah; Özpolat, Bülent; Ay, Mehmet; Şahiner, Nurettin
    Porous and biodegradable hyaluronic acid (HA) nanogel and their copolymeric forms with sucrose (Suc), HA:Sucrose (HA:Suc) nanogels, were synthesized by employing glycerol diglycidyl ether (GDE) as crosslinker with a single step reaction in surfactant-free medium. The size of the nanogels was determined as 150 +/- 50 nm in dried state from SEM images and found to increase to about 540 +/- 47 nm in DI water measured with DLS measurements. The surface areas of HA and HA:Suc nanogels were measured as 18.07 +/- 2.4 and 32.30 +/- 6.1 m(2)/g with porosities of 3.58 +/- 1.8, and 9.44 +/- 3.1 nm via BET analysis, respectively. The zeta potentials for HA and HA:Suc nanogels were measured as -33 +/- 1.4 and -30 +/- 1.2 mV, respectively. The thermal degradation of both types of nanogels revealed similar trends, while hydrolytic degradation of the nanogels was about 22.7 +/- 02 wt% in 15 days. Both HA and HA:Suc nanogels were stable in blood up to 250 mu g/mL concentration with approximately 0.5 +/- 0.1% hemolysis ratio and 76 +/- 12% blood clotting indices, respectively. Finally, these nanogels were used as a sustained slow-release or long-term delivery system over 2 days for a hydrophobic cancer drug, 3-((E)-3-(4-hydroxyphenyl)acryloyl)-2H-chromen-2-on (A(#)) established by our group. The nanogels successfully delivered the model drug A at 10.43 +/- 2.12 mg/g for 2 days. (C) 2019 Elsevier B.V. All rights reserved.
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    In vitro drug release studies for the treatment of TNBC and pancreatic cancers from natural derivated polymeric micro- and nano-particles
    (Amer Chemical Soc, 2018) Cömert Önder, Ferah; Sağbaş, Selin; Ay, Mehmet; Özpolat, Bülent; Şahiner, Nurettin
    [Anstract Not Available]
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    Major Bioactive Prenylated Flavonoids from Humulus lupulus L., Their Applications in Human Diseases and Structure-Activity Relationships (SAR) - A Review
    (Tabriz University of Medical Sciences, 2024) Cömert Önder, Ferah; Kalın, Sevil; Şahin, Nebahat; Davutlar, Gülce; Abusharkh, Khaled A.N.; Maraba, Özlem; Ay, Mehmet; Hal, Rabia Selina
    In recent years, the incidence of cancers, inflammatory diseases, Alzheimer's disease, glucose metabolism disorder and diabetes has increased alarmingly which demands more research into the discovery of new drug candidates to treat these human diseases. Main phytochemicals from Humulus lupulus L. (hops) have been demonstrated to have positive impacts on human health, and prenylated flavonoids are one of the major groups of bioactive phytochemicals found in this plant. Thus, this review summarizes the role of major prenylated components in hops in human diseases including cancer, inflammation and viral infections. In silico studies of prenylated bioactive compounds against various drug targets such as histone deactylases (HDACs), sirtuins (SIRTs), and acetylcholinesterase (AChE), and the molecular molecular interactions between protein and ligand have also been included. Furthermore, the structure-activity relationships (SAR) studies on these compounds are highlighted. This review concludes that the prenylated phytochemicals from H. lupulus L., including xanthohumol (XN), isoxanthohumol (IXN), 8-prenylnaringenin (8-PN) and 6-prenylnaringenin (6-PN), have promising roles in human health and may contribute to new drug discovery and development.
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    Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties
    (John Wiley and Sons Inc, 2023) Cömert Önder, Ferah; Şahin, Nebahat; Davutlar, Gülce; Önder, Alper; Ay, Mehmet
    In this study, the concept of combined in vitro and in silico studies were utilized by using some synthesized nitro bearing compounds. The anticancer activities of the studied compounds were performed by using colony formation analysis, cell cytotoxicity, and migration. Nitro group containing two compounds were analyzed using Hoechst staining to indicate the morphological changes on the nuclei of cancer cells under fluorescence microscopy. Scanning electron microscopy (SEM) analysis was performed with N,N-dibutyl-nitro-substituted compound. Nitro containing anticancer agents were shown the inhibition at 1.5 μM and 2 μM concentrations, and nuclear apoptosis was detected. In addition, cell-to-cell interaction on MDA-MB-231 cells was broken and observed morphologic changes following the treatment with N,N-dibutyl-nitro-substituted compound at the effective doses. In general, the other nitro compounds showed cell cytotoxicity at 5 μM, 10 μM, and 20 μM. Two hits as anticancer agents were determined as potential interleukin-1 receptor-associated kinase 1 (IRAK1) and interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor candidates. Molecular docking and molecular dynamics (MD) simulations studies will provide that the binding patterns with specific residues such as Met265, Tyr284 of the IRAK family members, and these will contribute to further in vitro and in vivo studies for targeted breast cancer therapy.
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    Novel inhibitors of eukaryotic elongation factor 2 kinase: In silico, synthesis and in vitro studies
    (Academic Press Inc., 2021) Cömert Önder, Ferah; Durdagi, Serdar; Kahraman, Nermin; Uslu, Tuğce Nur; Kandemir, Hakan; Ay, Mehmet
    Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual alpha kinase whose expression is highly upregulated in various cancers and contributes to tumor growth, metastasis, and progression. More importantly, eEF2K expression is associated with poor clinical outcome and shorter patient survival in breast, lung and ovarian cancers. Therefore, eEF2K is an emerging molecular target for development of novel targeted therapeutics and precision medicine in solid cancers. Currently, there are not any available potent and specific eEF2K inhibitors for clinical translation. In this study, we designed and synthesized a series of novel compounds with coumarin scaffold with various substitutions and investigated their effects in inhibiting eEF2K activity using in silico approaches and in vitro studies in breast cancer cells. We utilized an amide substitution at position 3 on the coumarin ring with their pharmacologically active groups containing pyrrolidine, piperidine, morpholine and piperazine groups with [sbnd](CH2)2[sbnd] bridged for aliphatic amides. Due to their ability to form covalent binding to the target enzyme, we also investigated the effects of boron containing groups on functionalized coumarin ring (3 compounds) and designed novel aliphatic and aromatic derivatives of coumarin scaffolds (10 compounds) and phenyl ring with boron groups (4 compounds). The Glide/SP module of the Maestro molecular modeling package was used to perform in silico analysis and molecular docking studies. According to our combined results, structure activity relationship (SAR) was performed in detail. Among the newly designed, synthesized, and tested compounds, our in vitro findings revealed that several compounds displayed a highly effective eEF2K inhibition at submicromolar concentrations in in vitro breast cancer cells. In conclusion, we identified novel compounds that can be used as eEF2K inhibitors and that they should be further evaluated by in vivo preclinical tumor models studies for antitumor efficacy and clinical translation.
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    Synthesis of SMZ derivatives and investigation of effects on germination, root, and plant growth of Arabidopsis thaliana L.
    (Tubitak Scientific & Technological Research Council Turkey, 2019) Güngör, Tuğba; Cömert Önder, Ferah; Sezer, Fatih; Özbilen, Aslıhan; Taşkın, Kemal Melih; Ay, Mehmet
    A series of sulfonamide derivatives were synthesized by reactions with various functional groups containing benzenesulfonyl chlorides and aniline derivatives under different substitution reaction conditions. The structures of SMZ derivatives were confirmed with melting point, FT-IR, H-1 NMR, C-13 NMR, and LC-MS/MS techniques. In order to investigate the cytotoxic effects of these derivatives, we used a model plant species. The synthesized compounds (S1-S5) and sulfamethazine (SMZ) as a positive control were applied to Arabidopsis thaliana seeds. Our results indicated that S3 and S4 induced shorter roots and lower wet weight in plants. Plants treated with S2 and S5 showed no growth effects, similar to the untreated control group, while S1 slightly reduced root length and wet weight. These results suggest that S3 and the newly synthesized S4 derivatives have potential for use as herbicides since they possess cytotoxic effects on A. thaliana plants.
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    Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo
    (Amer Chemical Soc, 2021) Cömert Önder, Ferah; Kahraman, Nermin; Bellur Atıcı, Esen; Çağır, Ali; Kandemir, Hakan; Tatar, Gizem; Ay, Mehmet
    Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another a-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors.