Browsing by Author "Cevik, Ozge"

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Design and Synthesis of Thiosemicarbazides and 1,2,4-Triazoles Derived From Ibuprofen as Potential Metap (Type II) Inhibitors
(Elsevier Ireland Ltd, 2025) Yilmaz, Ozgur; Biliz, Yagmur; Ayan, Sumeyra; Cevik, Ozge; Karahasanoglu, Mufide; Cotuker, Reyhan; Kucukguzel, S. . Guniz
In the present study, a range of novel thiosemicarbazides 4a-i and 1,2,4-triazoles 5a-i derived from ibuprofen, were synthesized. Structural elucidation of these synthesized compounds was performed utilizing a variety of spectroscopic methods, including FTIR, 1H NMR, 13C NMR and HR-MS. The synthesized compounds were tested for cytotoxicity in five different cancer cell lines (cervical cancer (HeLa), human breast cancer (MCF-7), human gastric adenocarcinoma (MKN-45), human metastatic prostate cancer (PC3) and human glioblastoma (U87)). The compounds were compared with healthy cells (NIH-3T3) and the most effective compounds were determined by means of the selectivity index. Thiosemicarbazides derived form ibuprofen 4i and 4d showed anticancer activity, while 1,2,4-triazoles derived form ibuprofen 5b, 5c, 5d, 5e, 5h, 5g showed anticancer activity in HeLa, MCF-7, MKN-45, PC3 and U87 cells. To test the stability of the protein-drug complexes all 18 compounds 4a-i and 5a-i were docked into the active site of the MetAP2 enzyme In general, computational inhibition constants values were correlated with the experimental values. The dynamic behavior of MetAP2-inhibitor complexes was analyzed using all atoms Molecular Dynamic (MD) simulations for 200 ns duration. MD revealed that the drugs bind in the active center of MetAP2 with stable RMSD and RMSF. In conclusion, in-silico results and in-vitro studies suggests that thiosemicarbazides and 1,2,4-triazoles derived from ibuprofen may be novel anticancer drug candidates for treating cervical, breast, prostate, gastric and glioblastoma. Compounds provided induction of apoptotic proteins in the cell by inhibiting MetAP2 enzyme. Furthermore, the potential antioxidant activities of the compounds were evaluated using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay. Among the compounds tested, 4a, 4b, 4e, 4f, 4h, and 4i exhibited values closely resembling the DPPH activity of the standards.
Citation - WoS: 10
Novel Azole-Urea Hybrids as Vegfr-2 Inhibitors: Synthesis, In Vitro Antiproliferative Evaluation And In Silico Studies
(Elsevier, 2023) Shirzad, Mohammad Musa; Kulabas, Necla; Erdogan, Omer; Cevik, Ozge; Dere, Damla; Yelekci, Kemal; Kucukguzel, Ilkay
The vascular endothelial growth factor receptor-2 (VEGFR-2) is a receptor tyrosine kinase known to be abnormally expressed in various malignant tumors, including breast cancer, and is considered one of the most important contributors to tumor angiogenesis. Sorafenib is one of many VEGFR-2 inhibitors that have received approval for clinical use from the US FDA in recent years. Accordingly, in this study, the synthesis of two new pyrazoles, six 1,3,4-oxadiazoles, four 1,3,4-thiadiazoles, and ten 1,2,4-triazole-3-thione derivatives having structural characteristics similar to sorafenib was carried out. A preliminary screening of synthesized compounds and known inhibitors sorafenib and staurosporine at 10 mu M concentration on in vitro activity of VEGFR-2 was performed, and compounds 10c, 8a, and 11 g were identified as the most potent derivatives with% VEGFR-2 residual activities lower than 30%, and dose-dependent inhibition studies was carried out to determine the IC50 values of these inhibitors. Compound 10c was found to be the most potent inhibitor of VEGFR-2 activity with an IC50 value of 0.664 mu M. The anti-proliferative activity of synthesized derivatives was assessed against a breast carcinoma (MCF-7) cell line, a triple negative human breast adenocarcinoma (MDA-MB-231) cell line, and noncancerous fibroblast cells (L929). Compound 8a displayed superior activity when compared to sorafenib against MCF-7 (7.69 fold) and MDA-MB-231 (1.52 fold) cell lines while displaying 3.75-fold less toxicity against the normal L929 cell line. Annexin V binding assay revealed that compound 8a significantly increased early and late apoptosis in MCF-7 cells and late apoptosis and necrosis in MDA-MB-231 cells. Computational studies such as molecular docking and ADMET evaluation were performed to elucidate the binding interactions and druglikeness of the synthesized compounds. The results indicate that compound 8a could be a promising candidate for the development of a novel anti-angiogenic and anti-proliferative agent.