Browsing by Author "Arzuk, Ege"

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Design, Synthesis, and Antiproliferative Activities of Novel Thiazolyl-Pyrazole Hybrid Derivatives
(Springer Birkhauser, 2023) Kuzu, Burak; Erguc, Ali; Karakus, Fuat; Arzuk, Ege
In this study, a series of derivatives of thiazolyl-pyrazole hybrid structures were designed to search for new heterocyclic compound-based antitumor agents. The designed target structures were synthesized with easy, practical, and efficient procedures. The antiproliferative effect of the synthesized compounds against cancer cell lines A549, MCF-7, and HepG2 was evaluated regarding inhibition concentration and selectivity index against healthy cell line CCD-34Lu. The results overall showed that the compounds had high antiproliferation against cancer cells compared to the doxorubicin-positive control. In particular, compound 11 A549 (SI: 3.58) and HepG2 (SI: 12.36) had high selectivity in cancer cell lines, while compounds 10h and 10o had high selectivity (SI: 10.74 for both) in MCF-7 cancer cell lines. The calculated theoretical pharmacokinetic properties revealed that they could be suitable drug candidates. In addition, in vitro test results indicate a correlation between the structure-activity relationships of the compounds. The various molecular modifications of thiazolyl-pyrazole hybrid compounds are promising for developing new anticancer drug candidates.
Discovery of New Pyrazole-Tosylamide Derivatives as Apoptosis Inducers Through Bcl-2 Inhibition and Caspase-3 Activation
(Wiley-v C H verlag Gmbh, 2025) Kuzu, Burak; Arzuk, Ege
In this presented study, a series of new carbonitrile-substituted pyrazole-tosyl amide derivatives were designed and synthesized according to previous studies. The antiproliferative effects of the synthesized compounds on MDA-MB-231, MCF-7, HepG2, PC-3, and A549 cancer cell lines were assessed by MTT assay compared with non-cancerous cells. The results demonstrate that compounds 9d, 9e, and 9f had a higher antiproliferative effect (IC50 <10 mu M) against both breast cancer cells. To investigate the ability of these compounds (9d-f) to induce apoptosis against breast cancer cells, BCL-2 levels and Caspase-3 activities of compound-treated breast cancer cell lines were measured by ELISA. The results revealed that these compounds significantly inhibited the levels of anti-apoptotic protein BCL-2 and increased the activity of apoptotic protein Caspase-3 in MDA-MB-231 and MCF-7 cells. Molecular docking studies confirmed that the selected compounds have high binding affinity towards the active site in the crystal structures of BCL-2 and Caspase-3. Moreover, drug-likeness and pre-ADMET evaluation showed that the compounds had suitable drug properties. This study may be a new milestone in terms of the promising importance of carbonitrile-substituted pyrazole-tosyl amide scaffolds as apoptosis-inducing agents for cancer therapy in the future.
Exploring the Role of Quercetin on Doxorubicin and Lapatinib-Mediated Cellular and Mitochondrial Responses Using in Vitro and in Silico Studies
(Taylor & Francis Ltd, 2025) Erguc, Ali; Albayrak, Gokay; Muhammed, Muhammed Tilahun; Karakus, Fuat; Arzuk, Ege; Ince-Erguc, Elif
Doxorubicin (DOX) and lapatinib (LAP) have been reported to cause liver toxicity. The roles of mitochondrial and cellular responses in DOX and LAP mediated-hepatotoxicity have not been investigated with or without quercetin (QUE) in HepG2 cells sensitive to mitochondrial damage (high-glucose or galactose media) in addition to in silico studies. Our results revealed that cytosolic pathways might play role a in DOX-induced cytotoxicity rather than mitochondria. QUE exacerbated DOX-induced ATP depletion in both environments. Our data also indicated that cytosolic and mitochondrial pathways might play a role in LAP-induced cytotoxicity. Incubating QUE with LAP increased ATP levels in high-glucose media. Therefore, QUE might have protective effect against LAP-induced cytotoxicity resulting from cytosolic pathways. The findings from in vitro experiments that QUE increased DOX or LAP-induced mitochondrial dysfunction were confirmed by the results from in silico studies indicating that QUE incubated with LAP or DOX might increase mitochondrial dysfunction.
Mitochondrial Impact of Organophosphate Pesticide-Induced Cardiotoxicity: an in Silico and in Vitro Study
(Sage Publications inc, 2024) Karakus, Fuat; Arzuk, Ege; Erguc, Ali
Organophosphate pesticides are widely used; however, their use is limited due to neurotoxicity and, to a lesser extent, cardiotoxicity in humans. Given the high energy demands of cardiac muscle, which is characterized by a dense population of mitochondria, any damage to these organelles can exacerbate cardiotoxicity. This study aims to elucidate whether the cardiotoxic effects of organophosphate pesticides originate from mitochondrial dysfunction. To investigate this, in silico toxicogenomic analyses were performed using various tools, such as the Comparative Toxicogenomic Database, GeneMANIA, STRING, and Cytoscape. Results revealed that 11 out of the 13 WHO-recommended Class Ia organophosphate pesticides target genes associated with cardiotoxicity. Notably, three of these genes were mitochondrial, with catalase (CAT) being the common differentially expressed gene among parathion, methyl parathion, and phorate. Furthermore, protein-protein interaction analysis indicated a strong association between CAT and superoxide dismutase 2, mitochondrial (SOD2). Subsequently, isolated heart mitochondria were utilized to assess CAT and superoxide dismutase (SOD) activities in vitro. The findings demonstrated that at a concentration of 7.5 ng/mu L, both methyl parathion and phorate significantly decreased CAT activity by approximately 35%. Moreover, phorate reduced total SOD and SOD2 activities by 17% and 19%, respectively, at the same concentration. In contrast, none of the three organophosphate pesticides induced the opening of the mitochondrial permeability transition pore. These results suggest that the reduction in CAT and SOD2 activities, critical antioxidant enzymes, leads to the accumulation of reactive oxygen species within mitochondria, ultimately resulting in mitochondrial damage. This mechanism likely underlies the observed cardiotoxicity induced by these organophosphate pesticides.
Mitochondrial Toxicity of Selected Natural Compounds: in Vitro Assessment and in Silico Molecular Docking and Dynamics Simulation
(Taylor & Francis Ltd, 2025) Erguc, Ali; Albayrak, Gokay; Muhammed, Muhammed Tilahun; Karakus, Fuat; Arzuk, Ege
Prangos uechtritzii Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate in vitro and in silico models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. In vitro results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The in silico study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.
Novel Pyrazole Derivatives Bearing Carbonitrile and Substituted Thiazole Moiety for Selective Cox-2 Inhibition
(Wiley-v C H verlag Gmbh, 2024) Arzuk, Ege; Karakus, Fuat; Erguc, Ali; Kuzu, Burak
In this study, a series of derivatives of pyrazole hybrid structures containing carbonitrile and substituted thiazole moiety were designed to search for selective COX-2 inhibition. The designed target structures were synthesized with easy, practical, and efficient procedures. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines for inhibition concentration and selectivity index. The results showed that the compounds have an inhibitory effect with higher selectivity towards COX-2 overall in both cell lines and moderate antiproliferative activity by targeting the breast cancer cell line MDA-MB-231. Among the 19 compounds synthesized (19 a-t), especially compound 19 m was found to be highly effective with COX-2 inhibition of 5.63 mu M in the NIH/3T3 cell line and 4.12 mu M in the MDA-MB-231 cell line. Moreover, molecular docking studies showed that the compounds indeed exhibited higher affinity for the COX-2 active site. The theoretical ADMET properties of the presented compounds were calculated, and the results showed that the compounds may have a more favorable pharmacokinetic effect profile than the selective COX-2 inhibitor Celecoxib, thus promising COX-2 inhibitor drug candidates for the future. A series of derivatives of pyrazole hybrid structures were designed to search for selective COX-2 inhibition. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines. Moreover, molecular docking, SAR, and ADMET studies showed that the compounds may have a more favorable pharmacokinetic profile, thus promising COX-2 inhibitor drug candidates for the future.image
Oksipösedanin Kaynaklı Antikanser Aktivitenin İn Siliko ve İn Vitro Değerlendirilmesi: Mitotoksisite
(2023) Baykan, Sura; Erguc, Ali; Okur, Hayati; Karakuş, Fuat; Albayrak, Gökay; Arzuk, Ege
Amaç: Çalışmanın amacı, farklı ortamlarda Oksipösedanin (OKS) aracılı antikanser aktivitedeki değişiklikleri değerlendirmektir. İkinci amaç, OKS’inin elektron transfer zincirine (ETZ) karşı afinitesini öngörmektir. Gereç ve Yöntem: MTT ve LDH sızma deneyleri OKS ile gerçekleştirilmiştir. Ayrıca, OKS’inin ETZ komplekslerine karşı afinitesini öngörmek için moleküler kenetlenme çalışmaları uygulanmıştır. Bulgular: Glukoz içeren ortamda 250 µM OKS canlılığı azaltmıştır. Galaktoz içeren ortamda ≥50 µM OKS hücre canlılığını azalmıştır. Galaktoz içeren ortamda ≥50 µM OKS membran parçalanmasını artırmıştır. Moleküler kenetlenme çalışmaları, OKS'inin Kompleks I ve IV'ün inhibisyon bölgelerine bağlanma kapasitesine sahip olabileceğini göstermektedir. Sonuç: Galaktoz içeren ortam, OKS aracılı sitotoksisiteyi artırmıştır. Ön sonuçlar, antikanser aktivitede mitotoksisitenin yer alabileceğini göstermektedir. Ayrıca OKS, Kompleks I ve IV'ün seçici inhibisyonu nedeni ile ETZ disfonksiyonuna neden olabilmektedir.
Role of Oxidative Stress and Reactive Metabolites in Cytotoxicity & Mitotoxicity of Clozapine, Diclofenac and Nifedipine in Cho-K1 Cells in Vitro
(Bentham Science Publ Ltd, 2023) Erguec, Ali; Karakus, Fuat; Arzuk, Ege; Mutlu, Neliye; Orhan, Hilmi
Background CHO-K1 cells were used as in vitro model to explore mechanisms of cytotoxicity of the test drugs. Aim To provide in vitro data on toxicity mechanisms of clozapine, diclofenac and nifedipine. Objective Cytotoxic mechanisms of clozapine (CLZ), diclofenac (DIC) and nifedipine (NIF) were studied in CHO-K1 cells in vitro. All three drugs induce adverse reactions in some patients with partially unknown mechanisms. Methods Following the determination of time- and dose-dependency of cytotoxicity by the MTT test, cytoplasmic membrane integrity was explored by the LDH leakage test. Both end-points were further examined in the presence of soft and hard nucleophilic agents, glutathione (GSH) and potassium cyanide (KCN), respectively, and either individual or general cytochrome P450 (CYP) inhibitors, whether CYP-catalysed formation of electrophilic metabolites play a role in the observed cytotoxicity and membrane damage. The generation of reactive metabolites during the incubations was also explored. Formation of malondialdehyde (MDA) and oxidation of dihydrofluorescein (DCFH) were monitored whether peroxidative membrane damage and oxidative stress take place in cytotoxicity. Incubations were also conducted in the presence of chelating agents of EDTA or DTPA to explore any possible role of metals in cytotoxicity by facilitating electron transfer in redox reactions. Finally, mitochondrial membrane oxidative degradation and permeability transition pore (mPTP) induction by the drugs were tested as markers of mitochondrial damage. Results The presence of an individual or combined nucleophilic agents significantly diminished CLZ- and NIF-induced cytotoxicities, while the presence of both agents paradoxically increased DIC-induced cytotoxicity by a factor of three with the reason remaining unknown. The presence of GSH significantly increased DIC-induced membrane damage too. Prevention of membrane damage by the hard nucleophile KCN suggests the generation of a hard electrophile upon DIC and GSH interaction. The presence of CYP2C9 inhibitor sulfaphenazole significantly diminished DIC-induced cytotoxicity, probably by preventing the formation of 4-hydroxylated metabolite of DIC, which further converts to an electrophilic reactive intermediate. Among the chelating agents, EDTA caused a marginal decrease in CLZ-induced cytotoxicity, while DIC-induced cytotoxicity was amplified by a factor of five. Both reactive and stable metabolites of CLZ could be detected in the incubation medium of CLZ with CHO-K1 cells, which are known to have low metabolic capacity. All three drugs caused a significant increase in cytoplasmic oxidative stress by means of DCFH oxidation, which was confirmed by increased MDA from cytoplasmic as well as mitochondrial membranes. The addition of GSH paradoxically and significantly increased DIC-induced MDA formation, in parallel with the increase in membrane damage when DIC and GSH combined. Conclusion Our results suggested that the soft electrophilic nitrenium ion of CLZ is not responsible for the observed in vitro toxicities, and this may originate from a relatively low amount of the metabolite due to the low metabolic capacity of CHO-K1. A hard electrophilic intermediate may contribute to cellular membrane damage incubated with DIC, while a soft electrophilic intermediate seems to exacerbate cell death by a mechanism other than membrane damage. A significant decrease in cytotoxicity of NIF by GSH and KCN suggested that both soft and hard electrophiles contribute to NIF-induced cytotoxicity. All three drugs induced peroxidative cytoplasmic membrane damage, while only DIC and NIF induced peroxidative mitochondrial membrane damage, which suggested mitochondrial processes may contribute to adverse effects of these drugs in vivo.
Synthesis of Thiazole-Integrated Pyrrolotriazinones: Evaluations of Cytotoxicity and Effects on P3ik Levels in Cancer Cells
(Tubitak Scientific & Technological Research Council Turkey, 2025) Kuzu, Eylem; Arzuk, Ege; Karakus, Fuat; Kuzu, Burak; Genc, Hasan
The synthesis of novel heterocyclic compounds, particularly those targeting critical signaling pathways in cancer, represents a promising approach to drug development. In this study, we designed and synthesized a series of thiazole-integrated pyrrolotriazinone derivatives, aiming to combine the antiproliferative properties of thiazole with the PI3K inhibitory activity of pyrrolotriazinones. The PI3K pathway, which plays a critical role in regulating cell growth, proliferation, and survival, is frequently dysregulated in cancer, making it an attractive target for therapeutic intervention. The synthesized derivatives were evaluated for their cytotoxic activities against MCF-7, A549, and HepG2 cancer cell lines. Their effect on PI3K protein levels was assessed to evaluate their potential as PI3K inhibitors. Preliminary results indicate that these thiazole-pyrrolotriazinone hybrids exhibit significant cytotoxic effects and may reduce PI3K protein levels in cancer cells. Furthermore, drug-likeness assessments and pre-ADMET evaluations demonstrated that the compounds exhibited promising characteristics, supporting their potential as viable drug candidates. Overall, this study highlights the potential of these novel compounds in cancer therapy and provides valuable insights into the design of small molecules that can target key regulatory pathways involved in cancer progression.