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Öğe Biological evaluation of benzothiazoles obtained by microwave-green synthesis(Acad Brasileira De Ciencias, 2024) Ozdincer, Mesut; Dalmaz, Aslihan; Durmus, Sefa; Dülger, Görkem; Kiliccioglu, IlkerBenzothiazole compounds are known as an important bicyclic ring system with multiple applications. These compounds have a wide range of biological activities, including anticancer, antimicrobial, anti-inflammatory and antiviral activities. In this study, benzothiazole compounds were synthesized and their various biological activities were examined. The synthesized benzothiazoles were evaluated for their antimicrobial properties against various bacterial and fungal strains. The compound 6e is most active ligand in the series against bacteria and fungi as compared to standard antibiotics. Especially, this compound significant effect against Staphylococcus aureus (32.00 +/- 1.73 mm). These compounds exhibited potent anticancer activity against gastrointestinal cancer cells, demonstrating their potential as therapeutic agents. The lowest antiproliferative response after administration of the compounds was observed in HCT116 cells, while the most effective antiproliferative response was observed in AGS cells (> 10 mu g/mL). In all cell lines, 40 and 100 mu g/mL application values of the selected compounds showed significant increases in the expression of caspase-3, 8 and 9. We also utilized a computational docking approach to investigate the interaction of these benzothiazoles with VEGFR-2 kinase. Our docking studies showed that compounds 6a and 6d may be promising therapeutic agents against gastrointestinal system cancers due to their ability to bind to VEGFR-2 kinase.Öğe Chemical composition, antioxidant, antimicrobial and anticancer activities of endemic Cephalaria tuteliana(Elsevier, 2024) Kiliccioglu, Ilker; Dülger, Görkem; Senturk, Fatih; Bozyel, Mustafa Eray; Canli, Kerem; Dülger, BaşaranIntroduction: The genus Cephalaria, belonging to the Caprifoliaceae family, is a rich source of secondary metabolites, including mainly saponins which display a variety of biological activities, such as antimicrobial, antioxidant, and anticancerous effects. This study was carried out to observe the biochemical composition and to evaluate the biological activities of Cephalaria tuteliana Kus & Gokturk. Methods: The composition of endemic C. tuteliana was determined through gas chromatography-mass spectrometry (GC-MS) studies. Antimicrobial effect were determined by the disk diffusion and dilution methods for test bacteria and test fungi. The antioxidant potential of the ethanol extract was also investigated. Cell proliferation and apoptosis analysis were investigated by WST-1 and ELISA methods. The migration level of PC-3 prostate cancer cells after plant extract application was examined by wound healing assay. Also, molecular docking experiments were performed to investigate the anticancer activity of the major component found in the C.tuteliana extract. Results: GC-MS analysis showed that the predominant compounds were Phenol, 2,20-methylenebis [6-(1,1dimethyl ethyl)-4-methyl- (23.54 %), 9,12,15-octadecatrien-1-ol, (Z,Z,Z)-(6.06 %) and n-Hexadecanoic acid (3.03 %). The ethanolic extract of C. tuteliana displayed moderate antimicrobial activity against a spectrum of tested microorganisms. Also, it exhibited significant antiproliferative effects on PC-3 human prostate cancer cells while having no harmful effects on healthy control HUVEC cells. Furthermore, enhanced expressions of Caspase-3, 8, and 9 were observed in PC-3 cells after plant extract treatment. Also, cell migration level was notably reduced, especially at a dose of 400 mg/mL in PC-3 cells. The DPPH free radical scavenging activity of ethanolic extracts of C. tuteliana showed higher activity than ascorbic acid. Molecular docking experiments showed potential binding of the major aromatic compound in C.tuteliana extract to human androgen receptor 1E3G protein. Conclusion: These findings highlight the potential of C. tuteliana as a valuable natural resource and pave the way for further in vivo prostate cancer investigations. (c) 2024 SAAB. Published by Elsevier B.V. All rights reserved.Öğe Comparative analysis of epi-miRNA expression levels in local/locally advanced and metastatic prostate cancer patients(Elsevier, 2020) Gurbuz, Venhar; Kiliccioglu, Ilker; Dikmen, Asiye Ugras; Bilen, Cenk Y.; Sozen, Sinan; Konac, EceAbnormal expression of enzymes involved in epigenetic mechanisms, such as DNA methyl transferases, can trigger large chaos in cellular gene expression networks and eventually lead to cancer progression. In our study, which is a pioneer in the literature that clinicopathologically evaluates the expression of 30 epi-miRNAs in prostate cancer (PCa), we investigated which of the new miRNA class epi-miRNAs could be an effective biomarker in the diagnosis and progression of PCa. In this study, the expression levels of 30 epi-miRNAs in whole blood samples from 25 control, 25 PCa and 40 metastatic PCa patients were investigated by the Quantitative Real-Time PCR method. Then, promoter methylation levels of 11 epi-miRNAs, whose expression levels were found to be significantly higher, were examined by methylation-specific qPCR method. The correlations between miRNA expression levels and clinicopathological parameters (Gleason Score (GS), PSA levels, TNM Staging) in different stages of PCa groups as well as disease-specific expression levels were examined. We found a hypomethylation in the promoter regions of miRNAs that showed a direct proportional increase with PSA levels (miR34b/c, miR-148a, miR-152), GS's (miR-34a-5p, miR-34b/c, miR-101-2, miR-126, miR-148a, miR-152, miR-1855p) and T staging (miR-34a-5p, miR-34b/c, miR-101-2, miR-126, miR-140, miR-148a, miR-152, miR-185-5p) (p < 0.05). When miR-200a/b was evaluated according to clinicopathological parameters, it acted as an oncomiR in local/local advanced PCa and as a tumor-suppressor-miR in metastatic stage. This study is novel in the sense that our findings draw attention to the important role of miRNAs as diagnostic and prognostic biomarkers in PCa.Öğe Cucurbitacin B and cisplatin induce the cell death pathways in MB49 mouse bladder cancer model(Sage Publications Ltd, 2020) Kurman, Yener; Kiliccioglu, Ilker; Dikmen, Asiye U.; Esendagli, Guldal; Bilen, Cenk Y.; Sozen, Sinan; Konac, EceCisplatin-based chemotherapy is the standard regimen for bladder cancer patients, but its effectiveness is limited by high toxicity and the development of drug resistance. It has been reported in many studies that Cucurbitacin B has anti-carcinogenic effects by stimulating apoptosis and autophagy. Here we explored the potential role of cucurbitacin B on MB49 bladder syngeneic mouse tumor model. Single and combined doses of cucurbitacin B and cisplatin were applied to MB49 cell line and the cell viability was determined by Water-Soluble Tetrazolium Salt-1 (WST) method. After developing the tumor model, mice were randomly divided into four groups and then cucurbitacin B and cisplatin applied in the specified doses and time. The expression levels of apoptosis (Bcl-2, Bax, Caspase-3, cleaved Caspase-3) and autophagy proteins (Beclin-1 and LC3I, LC3II) were detected by Western Blot. Phospho-protein array analysis was performed to determine the relative levels of phosphorylation of proteins which are associated with the PI3K-Akt signaling pathway. Tumor tissues were analyzed by hematoxylin-eosin staining. In the present study, the results showed that cucurbitacin B inhibited the expression of Bcl-2 and increased the expression of Bax and cleaved Caspase 3. LC3II is markedly up-regulated in cucurbitacin B-treated cells. Cucurbitacin B reduced the phosphorylation of p27, PRAS40, and Raf-1 proteins. CuB + Cis combination synergistically decreased phosphorylation of AKT, ERK1/ERK2, mTOR, BAD levels and increased the level of AMPK alpha. PI3K/AKT/ mTOR pathway might be one of the targets of cucurbitacin B in MB49 bladder cancer mouse model. CuB + Cis combination reduced the tumor growth. Cucurbitacin B has no toxic effects on lung, liver, kidney, heart, and bladder. Indeed, cucurbitacin B can inhibit the tumor proliferation; induce caspase-dependent/-independent apoptosis and autophagy. Our study provided a novel perspective to research the effects of cucurbitacin B on the apoptotic and autophagic pathways in bladder cancer and a new target class for drug development. Impact statement Alternative agents that will increase the effectiveness of cisplatin, which are widely used in the advanced stage and metastatic bladder cancer, are being investigated. In previous studies, Cucurbitacin B (CuB), which is a natural compound from the Cucurbitaceae family has been shown to inhibit the proliferation of tumor cells and create synergistic effects with cisplatin. In this study, we investigated the synergistic effect of CuB with cisplatin for the first time in bladder cancer in vitro and in vivo models. Our findings showed that CuB treatment with cisplatin reduced cell proliferation, and reduced tumor development through activating apoptosis and autophagy via PI3K/AKT/mTOR signaling pathway. Our results showed that CuB may be a new agent that can support conventional treatment in bladder cancer. Our study is important in terms of enlightening new pathways and developing new treatment methods in the treatment of bladder cancer.Öğe Dynamic serum biomarkers in infantile hemangioma: the role of VEGF-B, AKT, and eNOS in lesion regression(Springer, 2025) Cakmak, Hatice Mine; Kiliccioglu, Ilker; Dulger, GorkemInfantile hemangioma (IH) is the most common vascular tumor in infancy. This study aimed to investigate serum levels of VEGF-B, AKT, and eNOS in complicated versus uncomplicated cases of infantile hemangioma and evaluate their correlation with clinical regression scores over time. In this prospective study, we followed 64 patients with intrahospital hemorrhage (IH). Patients were grouped into two categories: complicated (n = 44) and uncomplicated (n = 20). Serum/plasma samples were collected on day 0 from all patients and on days 30 and 60 from complicated cases. ELISA techniques were used to quantify serum VEGF-B, AKT, and eNOS levels. A novel four-domain clinical regression scoring system (size, color, surface, and vascular activity; total 0-12 points) was developed and applied for the first 3 months of follow-up at each visit. VEGF-B, AKT, and eNOS serum levels were significantly higher at baseline in complicated IH and decreased over time with regression. However, AKT serum levels showed a significant decline only in the days of 60 (p = 0.043). Clinical regression scores increased in parallel, with substantial differences between healed and non-healed cases. ROC analysis revealed that day 30 and day 60 clinical scores strongly predicted complete healing (AUC = 0.739 and 0.850, respectively).Conclusion: The VEGF-B/VEGFR-1, AKT/mTOR, and eNOS pathways appear central to IH pathogenesis. Serum levels of these molecules may serve as dynamic biomarkers of disease phase and response to therapy. This study contributes novel data supporting potential targets for future personalized treatment strategies with a novel 3-month follow-up regression score predicting resolution.What is Known:center dot Angiogenic mediators such as VEGF-A, bFGF, Akt, and eNOS are elevated during the proliferative phase of infantile hemangioma and decline with propranolol treatment.center dot Previous studies have primarily investigated tissue-level expression, and there is limited clinical data on serum VEGF-B, Akt, and eNOS levels in IH patients.What is New:center dot This is the first clinical study to longitudinally measure serum VEGF-B, AKT, and eNOS levels in infantile hemangioma patients and track their changes during treatment-induced involution.center dot A novel, four-domain clinical regression scoring system (size, color, surface, vascular activity) was introduced and shown to predict treatment response within the first 60 days of follow-up.Öğe Evaluation of Benzothiazole-Chalcone Hybrids: Apoptosis Induction, Docking Analysis, and Anticancer Potential in Gastric Cancer Cells(Springer, 2025) Kiliccioglu, Ilker; Dulger, Gorkem; Musatat, Ahmad Badreddin; Atahan, Alparslan; Caliskan, Emel; Alpay, Merve; Zengin, MustafaThis study investigated a series of chalcone derivatives containing benzothiazole groups (C1-7) for their antimicrobial, antioxidant, and anticancer potential against gastrointestinal cancer cell lines. The compounds showed the highest antiproliferative effect in AGS gastric cancer cells compared to HCT116 colon cancer and HepG2 hepatocellular carcinoma cells. Among the tested compounds, C3 and C4 exhibited the most potent antiproliferative effects (IC50 = 7.55 mu g/mL and 8.25 mu g/mL at 48 h, respectively), significantly outperforming Cisplatin (IC50 = 15.71 mu g/mL). Mechanistic investigations revealed that C3 and C4 induce apoptosis by upregulating caspase-3, -8, and -9, suppressing anti-apoptotic Bcl-2, and elevating pro-apoptotic Bax and p53 proteins. These compounds also impeded AGS cell migration. Antimicrobial evaluations demonstrated an effective profile against multi-drug resistant bacteria, and their effects were comparable to those of the reference antibiotic Ciprofloxacin (< 0.5 g/mL). Antifungal activity results showed that MIC values ranged from < 0.5 to 256 mg/mL. Antioxidant profiling identified C1 as the most potent antioxidant, while C3 exhibited a unique dual role as an oxidant and pro-apoptotic agent. DFT computational studies harmonized the experimental findings, with molecular docking revealing high binding affinities of C3 and C4 to apoptosis regulators Bcl-2 and survivin. ADME predictions affirmed favorable drug-likeness, with moderate solubility, optimal distribution, and synthetic feasibility. This study provides a robust framework for developing benzothiazole-chalcone hybrids as precision therapeutics, positioning C3 and C4 as promising candidates for gastric cancer therapy.Öğe Synergistic fusion of carbazole, quinoline, and chalcone scaffolds: A computational and experimental exploration of hybrid compounds as selective anticancer agents(Elsevier, 2025) Musatat, Ahmad Badreddin; Kiliccioglu, Ilker; Louaileche, Tinhinane; Dulger, Gorkem; Maouche, Chaima; Tabti, Salima; Kurman, YenerNovel carbazole-quinoline-chalcone hybrids (nQCC1-4) were synthesized via Claisen-Schmidt condensation and evaluated against AGS gastric adenocarcinoma cells. The most potent compound, 1QCC-1, exhibited significant antiproliferative activity (IC50 values of 19.11 mu g/mL and 7.91 mu g/mL at 24 h and 48 h). Compounds 1QCC-4, 1QCC-3, and 2QCC-2 demonstrated comparable cytotoxic efficacy against AGS cells. Density functional theory (DFT) calculations revealed substituent-dependent electronic properties, with chloro-quinoline derivatives displaying enhanced electrophilicity (omega = 13.745-14.157 eV) and reduced HOMO-LUMO gaps (Delta E = 3.304-3.347 eV), correlating with improved bioactivity profiles. Molecular docking studies identified robust binding interactions with oncogenic targets, MAPK1 p38 kinase, HER2, and RhoA, with 1QCC-4 exhibiting superior binding affinity for HER2 (Delta G = -12.05 kcal/mol, IC50 = 1.48 nM) through hydrogen bonding with Lys114 and it-alkyl interactions with Leu156. ADMET profiling highlighted favorable drug-likeness parameters despite solubility challenges (LogS = -7.846 to -6.291) and potential CYP450 inhibition. Non-covalent interaction (NCI-RDG) and molecular electrostatic potential (MEP) analyses elucidated key stabilizing interactions and nucleophilic/electrophilic hotspots. These hybrids represent a strategic integration of natural product pharmacophores, leveraging synergistic electronic and steric effects for selective kinase inhibition, positioning them as promising leads for targeted gastric cancer therapy.
