Browsing by Author "Erguc, Ali"

Now showing 1 - 7 of 7

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.
Design, Synthesis, and Evaluation of Benzoxazole-Linked Pyrazole Hybrids as VEGFR-2 Antiproliferative Agents
(Humana Press inc, 2025) Deniz, Elif; Coven, Furkan Ozan; Erguc, Ali; Karakus, Fuat; Kuzu, Burak
In this study, a series of benzoxazole-linked pyrazole compounds (20a-t) were synthesized and tested for their antiproliferative activity. Their effects on lung cancer (A549) and normal lung (CCD-34Lu) cell lines were evaluated using the MTT assay. Among them, compounds 20m and o showed strong antiproliferative effects, with IC50 values of 7.64 and 15.82 mu M, respectively, and selectivity indices of 2.84 and 1.95 in favor of cancer cells. ELISA tests demonstrated that both compounds statistically significantly reduced VEGFR-2 protein levels by 24.8 and 28.7% at their respective IC50 values, indicating potential antiangiogenic properties. Molecular docking studies supported these findings by showing favorable binding of 20m and o to the VEGFR-2 receptor, with binding energies of -7.33 kcal/mol and -7.22 kcal/mol, respectively. Overall, compounds 20m and o stand out as promising candidates for further development as anticancer drugs.
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.