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    Anticancer Activity-Structure Relationship of Quinolinone-Core Compounds: An Overall Review
    (Springer, 2023) Beker, Hueseyin Kerim; Yildirim, Isil
    Quinolinone/quinoline is one of the most unique structures in the discovery of heterocycles that have attracted much attention in the field of medicinal chemistry. The basic scaffold of fused quinoline derivatives is of great interest to medicinal chemists since large road maps of the gene and protein expression can be used to classify cancers or predict responses to certain types of treatments targeting the level of both transcription and translation and the level of enzyme activity. These specific regulations may open the door for the discovery of new drug candidates including anticancer targets. This review provides a comprehensive description of various quinolinone derivatives, especially by concentrating on compounds containing benzimidazole rings. Quinolone moieties are experimentally proven anticancer pharmacophores which may further enhance their activity due to various functional groups, mostly the electron-withdrawing groups such as fluoro, chloro, nitro, amino, and carbonyl groups that showed stronger activity than those with electron-donating groups such as methyl and methoxy groups. The presence of an electron-withdrawing or electron-donating group at the quinolone ring influences the redox properties affecting DNA synthesis. Structural motifs attributed to noteworthy inhibitory results are identified and highlighted to encourage further research and drug development. This work aims to help researchers in discovering more powerful, active, and less toxic quinoline-based anticancer drugs and developing new vision in the search for their rational design.
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    Cynarine Exhibits Antiproliferative Activity and Bcl-2-Mediated Apoptotic Cell Death in Breast Cancer Cells
    (Springer, 2024) Ozdem, Berna; Yildirim, Isil; Cetin, Ayten Kilincli; Tekedereli, Ibrahim
    Cynarine is a biologically active compound that is a derivative of hydroxycinnamic acid and can exhibit a structure-function relationship and therapeutic potential due to its bioactive properties. This study aimed to investigate the antiproliferative and apoptosis activity of the Cynarine compound in breast cancer cells in vitro. MDA-MB-231 MCF7 breast cancer cells and MCF 10A non-cancer cells were used. The MTT method was used to evaluate cell viability. Acolony-forming assay was employed on the cells treated with cynarine to assess their colony-forming capability. Western blotting and annexin-propidium iodide methods with flow cytometry were used to clarify its role in apoptosis. Cell proliferation and colony-forming abilities were reduced in cynarine-treated cells at 56.2%, 67, and 3% in MCF7 and MDA-MB 231, respectively. Apoptotic cell rates after 72 hours of cynarine treatment were found at 7.15%, 42.94%, and 68.67% in MCF 10A, MCF7, and MDA-MB-231 cell lines, respectively. Apoptosis was significantly different in MDA-MB-231 and MCF7 cells treated with cynarine (p < 0.05) It has been concluded that cynarine can be used as a combination therapeutic or a precursor compound to develop new drug combinations to treat breast cancer.
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    Cytotoxic activity and apoptosis induction by a series Ag(I)-NHC complexes on human breast cancer cells and non-tumorigenic epithelial cell line
    (Elsevier, 2021) Kutlu, Turkan; Yildirim, Isil; Karabiyik, Hande; Kilincli, Ayten; Tekedereli, Ibrahim; Gok, Yetkin; Dikmen, Miris
    The main problems encountered in treatment with anticancer drugs, undesired side effects, and toxicity. One of the most important parameters in cell transport is the lipophilic and solubility property of the drug. Enough with the potential effects, side effects with minimal demand for new anti-cancer compounds, mechanisms of action of the compound can meet because of increased efforts to be clarified. In this case, scientists were encouraged to do new research. In particular, the organometallic compounds are one of the topics focused lately. Ag(I)-NHC complexes are one of the most important classes of organometallic compounds. Although the anticancer activity of Ag(I)-NHC complexes have been known recently times, the anticancer effects of 2-morpholino ethyl substituted benzimidazolium derivative, lipophilic, and solubility properties. Ag(I)-NHC complexes have not unknown yet. Therefore, we aimed to investigate of cytotoxic effect and apoptosis mechanism on breast cancer cell lines (MCF7), breast adenocarcinoma cell lines (MDA-MB-231), and non-tumorigenic epithelium cell lines (MCF 10A) of new Ag(I)-NHC complexes that derivative from morpholine-linked benzimidazole, were synthesized and antimicrobial activity was determined in our previous study. The cytotoxicity was determined by the MTS method, and the apoptosis mechanisms were determined the cell cycle, Annexin V, and caspase-3 analysis. A new benzimidazolium salt bearing morpholino ethyl substituent (2) was synthesized. This benzimidazolium salt was characterized by NMR and FT-IR spectroscopic method and elemental analysis technique. Also, the structure of the new benzimidazolium salt was confirmed by single-crystal X-ray diffraction. Ag(I)-NHC complexes inhibited the growth of MCF7 and MDA-MB-231 cells depending on the dosage and time. The complexes 3a and 3b exhibited a significant difference p < 0.05; p < 0.001; and p < 0.001 level depend on depending on the increase in concentration on cancer cells. All compound induced by apoptosis was associated with stopping the cell cycle in phase G1 and the caspase-3 activity exhibited. The complex 3c was the lowest number of caspase-activating cells (2.1%) compared with both the control and other complexes in MDA-MB-231 cells. But the complex 3a was the highest number of caspase-activating cells (% 9.6). These findings have shown that these new Ag(I)-NHC complexes can be important new anticancer agents for breast cancer treatments. (C) 2020 Elsevier B.V. All rights reserved.
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    The Cytotoxicity Profile, Apoptosis Mechanism, and Molecular Docking Studies of a Series of Benzimidazolium Derivative Morpholine-Substituted Ag(I) Heterocyclic Carbene Complexes
    (Springer, 2023) Kutlu, Tuerkan; Yildirim, Isil; Dikmen, Miris; Tok, Tugba Taskin; Aktas, Aydin; Gok, Yetkin
    The main problems experienced in treatment with anticancer drugs are undesirable side effects, and toxicity. Minimal side effects for new anticancer compounds may be met due to enhanced efforts to clarify the compound's mechanisms of action. Therefore, we aimed to investigate whether or the cytotoxic effect and apoptosis mechanism of a series Ag(I)NHC complexes on non-small cell lung cancer cell line (A549) and normal lung fibroblast cell line (CCD-19Lu) in this study. The cytotoxicity was determined by using the MTT method, and apoptotic effects were detected by cell cycle, annexin-V/propidium iodide (PI) staining and cell cycle, caspase-3, mitochondrial membrane potential analysis. Molecular docking studies were performed using in silico ADMET analysis, and molecular docking information on the compounds was gained using the DS 3.5 software subprotocol. All the time, the cytotoxic effect of silver compounds was monitored for 24 h in comparison to cisplatin. The apoptotic effect of these compounds increased in cancer cells as compared to normal cells. Complex 3b exhibited the highest cytotoxic activity on cancer cell in 24 and 72 h, but complex 3a exhibited the highest cytotoxic activity on cancer cell s in 48 h. Moreover, all Ag(I)NHC complexes exhibited significant statistical difference depending on the increase in concentration on cancer cells, and all compounds induced apoptosis associated with distributing of membrane polarization and stopping the cell cycle in phase G1 and the caspase-3 activity. Caspase-3 activity of the new Ag(I)NHC compounds showed 8.3 to 17.6-fold increase compared the untreated cells. The loss of mitochondrial membrane potential indicated that JC-1 assay results were 16.9 to17.2-fold higher than normal cells in Ag(I)NHC compounds and 11.3-fold higher her in cisplatin. In addition, molecular docking studies were executed on the Ag(I)NHC complexes, and cisplatin estimate that the binding modes towards the EGFR kinase. Because epidermal growth factor receptor (EGFR) is expressed highly in a great number of epithelial tumors. These findings suggested that Ag(I)NHC complexes exhibited anticancer activity and may be considered to have a new therapeutic potential for human non-small cell lung cancer cell treatment.
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    Expression analysis of novel long non-coding RNAs for invasive ductal and invasive lobular breast carcinoma cases
    (Elsevier Gmbh, 2023) Aktan, Cagda; Kucukaslan, Ali Sahin; Turk, Bilge Aydin; Yildirim, Isil
    Aim: Long non-coding RNAs (LncRNAs) serve as important regulatory molecules of gene expression and protein functionality at multiple biological levels, and their deregulation plays a key role in tumorigenesis including in breast cancer metastasis. Therefore, in this study, we aim to compare the expression of novel lncRNAs in the landscape of invasive ductal carcinoma (IDC) and invasive lobular (ILC) carcinoma of breast.Main Methods: We have designed an in-silico approach to find the lncRNAs that regulate the breast cancer. Then, we used the clinical samples to carry out the verification of our in silico finding. In the present study, the tissues of breast cancer were deparaffinized. RNA was extracted by the TRIzole method. After synthesizing cDNA from the extracted RNA, expression levels of lncRNAs were analyzed by qPCR using primers specifically designed and validated for the targeted lncRNAs. In this study, breast biopsy materials from 41 female patients with IDC and 10 female patients with ILC were examined histopathological and expression changes of candidate lncRNAs were investigated in line with the findings. The results were analyzed using IBM SPSS Statistics 25 version.Results: The mean age of the cases was 53.78 +/- 14.96. The minimum age was 29, while the maximum age was 87. While 27 of the cases were pre-menopausal, 24 cases were post-menopausal. The number of hormone receptor-positive cases was found to be 40, 35, and 27 for ER, PR, and cerb2/neu, respectively. While the ex-pressions of LINC00501, LINC00578, LINC01209, LINC02015, LINC02584, ABCC5-AS1, PEX5L-AS2, SHANK2-AS3 and SOX2-OT showed significant differences (p < 0.05), the expressions of LINC01206, LINC01994, SHANK2-AS1, and TPRG1-AS2 showed no significant differences (p > 0.05). In addition, it was determined that the regulation of all lncRNAs could be able to involve in the development of cancer such as the NOTCH1, NFKB, and estrogen receptor signalings.Conclusion: As a result, it was thought that the discovery of novel lncRNAs might be an important player in the diagnosis, prognosis and therapeutic development of breast cancer.