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    Design and synthesis of novel 1,2,3,4-tetrazines as new anti-leukemia cancer agents
    (WILEY, 2023-09-29) Eyilcim, Özgür; Günay, Fulya; Günkara, Ömer Tahir; Ng, Yuk Yin; Ulucan, Özlem; Erden, İhsan
    A series of novel 1,2,3,4-tetrazines were designed and synthesized. 1H-NMR spectroscopy, 13C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm-6, Reh, K562, and Molt-4) and one non-leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm-6, K562, Jurkat, and Molt-4 cell lines, IC50 values were found to be 15.98, 19.12, 23.15, and 25.80 & mu;M, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4-tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents. Eleven novel 1,2,3,4-tetrazine derivatives were synthesized via [3 + 3] cycloaddition reaction between in situ formed aza-oxyallyl cations and azides and their anticancer activities were evaluated against five different leukemia cell lines and one non-leukemic cell line. Compound 3a showed the best activity in all cell lines except the Reh cell line. Docking studies showed that DHFR could be a potential target protein for these new compounds and the binding structures of some compounds were investigated.image
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    Discovery of Potential PD-1 and PD-L1 Interaction Inhibitors Using Combined Molecular Modeling Approaches
    (Adiyaman University, 2025) Ulucan, Özlem
    Immune checkpoints are regulators of the immune system that maintain immune homeostasis and prevent autoimmunity. Cancer cells often manipulate immune checkpoint mechanisms to escape anti-tumor immune response by overexpressing the immune checkpoint ligands. Thus, the interactions between the immune checkpoint receptors and ligands attracted attention and were proven to be effective targets in treating cancer. In this study, combining several computational approaches, we discovered small molecules that effectively bind to the ligand Programmed Cell Death Ligand 1 (PD-L1) and have the potential to hamper its interaction with the negative immune checkpoint receptor Programmed Cell Death Protein-1 (PD-1). Different pharmacophore models were constructed using triple and quadruple combinations of the interface residues on PD-1, which were used later for scanning the ZINC15 database. 12714 small molecules were retrieved and virtually screened using molecular docking calculations. The complexes of promising small molecules with PD-L1 were further evaluated using energetic and structural analyses. Our results suggest that the three small molecules ZINC21075815, ZINC70692276, and ZINC64031730 retrieved from the ZINC15 database establish stable and energetically favorable interactions with PD-L1 at the hot region consisting of the residues Tyr 56, Glu 58, Arg 113, Met 115, and Tyr 123. These molecules can be used as a starting point to develop more effective and selective anti-PD-1/PD-L1 inhibitors. © 2025, Adiyaman University. All rights reserved.
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    Synthesis, molecular modeling, and biological evaluation of novel imatinib derivatives as anticancer agents
    (TUBITAK, 2022) Günay, Fulya; Yin, Ng. Yuk; Ulucan, Özlem
    Abstract: Different derivatives of imatinib were synthesized by a 3-step reaction method. The structures of the new compounds were characterized by spectroscopic methods. For quantitative evaluation of the biological activity of the compounds, MTT assays were performed, where four BCR-ABL negative leukemic cell lines (Jurkat, Reh, Nalm-6 and Molt-4), one BCR-ABL positive cell line (K562), and one non-leukemic cell line (Hek293T) were incubated with various concentrations of the derivatives. Although imatinib was specifically designed for the BCR-ABL protein, our results showed that it was also effective on BCR-ABL negative cell lines except for Reh cell line. Compound 9 showed lowest IC50 values against Nalm-6 cells as 1.639 µM, also the values of Compound 10 for each cell were very close to imatinib. Molecular docking simulations suggest that except for compound 6, the compounds prefer a DFG-out conformation of the ABL kinase domain. Among them, compound 10 has the highest affinity for ABL kinase domain that is close to the affinity of imatinib. The common rings between compound 10 and imatinib adopt exactly the same conformation and same type of interactions in the ATP binding site with the ABL kinase domain. © TÜBİTAK