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    Discovery of the aminated quinoxalines as potential active molecules
    (Bentham Science Publishers, 2024) Bener, Sedef; Bayrak, Nilüfer; Mataracı-Kara, Emel; Yıldız, Mahmut; Sever, Belgin; Tuyun, Amaç Fatih; Department of Molecular Biology and Genetics; Çiftçi, Halil İbrahim; Department of Molecular Biology and Genetics; College of Sciences
    Background: In recent years, as the biological activity of the quinoxaline skeleton has been revealed in numerous studies, interest in synthesizing new prototype molecules for the treatment of many chronic diseases, especially cancer, has increased. Methods: The desired alkoxy substituted aminoquinoxalines (AQNX1-9) were synthesized by the reaction of QNX and alkoxy substituted aryl amines such as 2-methoxyaniline, 4-methoxyaniline, 2ethoxyaniline, 3-ethoxyaniline, 4-ethoxyaniline, 4-butoxyaniline, 2,4-dimethoxyaniline, 3,4dimethoxyaniline, and 3,5-dimethoxyaniline according to the previously published procedure. QNX was aminated in DMSO at 130°C. We synthesized various alkoxy substituted aminoquinoxaline compounds (AQNX1-9) and evaluated their anticancer and antimicrobial activities in order to expand the search to related structures. In particular, two aminoquinoxaline (AQNX5 and AQNX6) compounds, coded as NSC D-835971/1 and NSC D-835972/1 by the National Cancer Institute in the USA, were screened for anticancer screening at a dose of 10-5 M on a full panel of 60 human cell lines obtained from nine human cancer cell types (leukemia, melanoma, non-small cell lung, colon, central nervous system, ovarian, kidney, prostate, and breast cancer). Results: Further in silico studies were also conducted for the compound AQNX5 (NSC D835971/1), which was found to be the most active antiproliferative agent, especially against leukemia cell lines. Molecular docking studies showed that AQNX5 interacted with Glu286 and Lys271 through hydrogen bonding and π-stacking interaction in the ATP binding region of Abl kinase, which is indicated as a potential target of leukemia. Besides, AQNX5 occupied the minor groove of the double helix of DNA via π-stacking interaction with DG-6. Conclusion: According to in silico pharmacokinetic determination, AQNX5 was endowed with drug-like properties as a potential anticancer drug candidate for future experiments. In the light of these findings, more research will focus on aminated quinoxalines' ability to precisely target leukemia cancer cell lines.
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    Unfolded protein response is involved in trans-platinum (ii) complex-induced apoptosis in prostate cancer cells via ros accumulation
    (2019) Karakaş, Didem; Oral, Arzu Y.; Yılmaz, Veysel T.; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A
    Background: Prostate cancer is one of the most common cancer types and it is the sixth leading cause of cancer-related death in men worldwide. Even though novel treatment modalities have been developed, it still a lifethreatening disease. Therefore novel compounds are needed to improve the overall survival. Methods: In our study, it was aimed to evaluate the anti-cancer activity of newly synthesized Platinum (II) [Pt(II)] complex on DU145, LNCaP and PC-3 prostate cancer cell lines. The cytotoxic activity of Pt(II) complex was tested by SRB and ATP cell viability assays. To detect the mode of cell death; fluorescent staining, flow cytometry and western blot analyses were performed. Results: The Pt(II) complex treatment resulted in a decrease in cell viability and increasing levels of apoptotic markers (pyknotic nuclei, annexin-V, caspase 3/7 activity) and a decrease in mitochondrial membrane potential in a dose dependent manner. Among cell types, tested PC-3 cells were found to be more sensitive to Pt(II) complex, demonstrating elevation of DNA damage in this cell line. In addition, Pt(II) complex induced Endoplasmic Reticulum (ER) stress by triggering ROS generation. More importantly, pre-treatment with NAC alleviated Pt(II) complex-mediated ER stress and cell death in PC-3. Conclusion: These findings suggest an upstream role of ROS production in Pt(II) complex-induced ER stressmediated apoptotic cell death. Considering the ROS-mediated apoptosis inducing the effect of Pt(II) complex, it warrants further evaluation as a novel metal-containing anticancer drug candidate.