Browsing by Author "Yelekci, Kemal"

Now showing 1 - 12 of 12

Citation Count: 0
Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs
(Frontiers Media Sa, 2022) Yelekçi, Kemal; Peng, Wenjing; Unruh, Daniel; Mayer, Michael F.; Mechref, Yehia; Yelekci, Kemal
Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.
Citation Count: 0
Docking of novel reversible monoamine oxidase-B inhibitors: Efficient prediction of ligand binding sites and estimation of inhibitors thermodynamic properties
(Amer Chemical Soc, 2006) Yelekçi, Kemal; Toprakci, Mustafa
[No Abstract Available]
Citation Count: 0
IN SILICO SCREENING OF NOVEL-POTENTIAL INHIBITOR OF METHIONINE AMINOPEPTIDASE 2 FOR THE TREATMENT OF CANCER
(Elsevier Science inc, 2024) Yelekçi, Kemal; Sahin, Naz Mina Mert
[No Abstract Available]
Citation Count: 0
In Silico Modeling of Dopamine Transporter and Design of Novel Neuroprotective Agents
(Amer Chemical Soc, 2016) Yelekçi, Kemal; Yelekci, Kemal
[Abstract Not Available]
Citation Count: 4
Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity
(Springer, 2022) Yelekçi, Kemal; Çiftçi, Gamze; Zhan, Chang-Guo; Ciftci, Gamze; Yelekci, Kemal; Gurboga, Merve; Ozakpinar, Ozlem Bingol
Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 mu M, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 mu M. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment. [GRAPHICS] .
Citation Count: 1
Novel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studies
(Elsevier, 2023) Yelekçi, Kemal; 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.
Citation Count: 0
Repurposing of known drugs from multiple libraries to identify novel and potential selective inhibitors of HDAC6 via in silico approach and molecular modeling
(Cell Press, 2024) Yelekçi, Kemal; Erdogan, Buse; Yelekci, Kemal
Histone deacetylase 6 (HDAC6, Class IIb) is a promising target for anticancer drugs. So far, few nonselective HDAC inhibitors have received regulatory approval as anticancer agents. However, they are associated with cell toxicity. Thus, isoform-selective inhibitors may be desirable. Here, we conducted structure-based virtual screening of multiple libraries containing a total of 2,250,135 compounds against HDAC6. The top hits with good docking scores and potential selectivity over HDAC10 (Class IIb) were submitted to 100 ns molecular dynamics simulation to monitor their dynamic behaviors and stability in the binding pockets of these enzymes. Furthermore, the drug-likeness and ADMET properties of these hits were estimated computationally. Four diverse compounds from different sources, including NCI and ZINC databases (BDH33926500, CID667061, Cromolyn, and ZINC000103531486), show potential selectivity for HDAC6.
Citation Count: 4
Screening of novel and selective inhibitors for neuronal nitric oxide synthase (nNOS) via structure-based drug design techniques
(Taylor & Francis inc, 2023) Yelekçi, Kemal; Yelekci, Kemal
NO, or nitric oxide, is produced by a family of enzymes called nitric oxide synthase (NOS) from L-arginine. NO regulates many physiological functions such as smooth muscle relaxation, immune defense, and memory function. The overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS) is implicated in neurodegeneration and neuropathic pain, making nNOS inhibition a promising therapeutic approach. Many developed nNOS inhibitors, generally L-arginine mimetics, have some issues in selectivity and bioavailability. According to earlier studies, targeting nNOS has the advantage of decreasing excess NO in the brain while avoiding the negative consequences of inhibiting the two isozymes: endothelial NOS (eNOS) and inducible NOS (iNOS). This study applied structure-based virtual screening, molecular docking, and molecular dynamics simulations to design potent and selective inhibitors against nNOS over related isoforms (eNOS and iNOS) using human X-ray crystal structures of the NOS isoforms. It was discovered that some compounds displayed a very good inhibitory potency for hnNOS and moderate selectivity for the other isozymes, eNOS and iNOS, in addition to good solubility and desirable physiochemical properties. The compounds which showed good stability and selectivity with nNOS, such as ZINC000013485422, can be interesting and informative guidance for designing more potent human nNOS inhibitors. Communicated by Ramaswamy H. Sarma
Screening of novel and selective inhibitors for neuronal nitric oxide synthase (nNOS) via structure-based drug design techniques
(Kadir Has Üniversitesi, 2022) boumezber, sarah; Yelekçi, Kemal; Yelekci, Kemal
The overproduction of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS) is the main cause of several neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Multiple Sclerosis (MS). NO is produced in many cell types by three isoforms of NOS (nNOS, iNOS, and eNOS) and has various biological functions, generally, for its significant reactivity with proteins. NOS isoforms share a high sequence and structure similarity, specifically in the active site, which makes the development and design of nNOS inhibitors extremely challenging; mainly, no-selective inhibitors can affect iNOS and eNOS physiological roles. To date, there is no selective inhibitor against nNOS in the market with desirable ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties, and pass the blood-brain barrier (BBB). With improvement of computational drug design techniques and accessibility of the X-ray crystal structures, development of novel drugs became less expensive and faster. Our research benefited from the structure-based drug design approaches to investigate proficient and selective inhibitors against nNOS. After structure-based virtual screening, the selective top-ranked compounds were filtered according to the ADMET prediction; then, the candidates with a high affinity with a suitable ADMET profile were subject to 100 ns molecular dynamics (MD) simulations. The stability through the 100 ns run has been evident for some nominated inhibitors, which are valuable lead compounds that can be optimized to reach the greatest physicochemical properties in addition to the selectivity.
Citation Count: 3
Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates
(Acg Publications, 2022) Yelekçi, Kemal; Kulabas, Necla; Guerboga, Merve; oezakpinar, Oezlem Bingoel; ciftci, Gamze; Yelekci, Kemal; Liu, Jianyang
Some novel triazole-bearing acetamide derivatives 9-26 were synthesized starting from carvacrol. All synthesized compounds were characterized by FTIR,1H-NMR,13C-NMR and MS data. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human chronic myelogenous leukemia K562, human neuroblastoma SH-SY5Y cell lines) were evaluated by MTT assay. Compounds were also tested on mouse embryonic fibroblast cells (NIH/3T3) to determine selectivity. Eighteen target compounds 9-26 were screened for their mPGES-1 and COX-1/2 inhibitory activities. Of these compounds, 26 (KUC16D425) showed the highest mPGES-1 inhibition at 10 mu M. This compound has also been observed to induce apoptosis and inhibit cell migration in MCF-7 cells. In silico molecular docking calculations were performed to understand the binding interactions of compounds with target proteins. ADMET predictions were also done to evaluate drug-like properties of the novel compounds.
Citation Count: 0
Synthesis and investigation of cytotoxic effects of compounds derived from flurbiprofen
(Elsevier, 2023) Yelekçi, Kemal; Dere, Damla; Bedir, Ipek; Yelekci, Kemal; Telci, Dilek; Kucukguzel, S. Guniz
New flurbiprofen derivatives containing 1,2,4-triazoline-5-thione (4) and thioethers (5a-r) were synthesized in this study. The structures of synthesized compounds were characterized by spectral methods (FT-IR, 1H NMR, 13C NMR) and 19F NMR (only compound 5l), besides elemental analysis. In addition, molecular binding of these compounds to the human methionine aminopeptidase 2 enzyme was performed using AutoDock 4.2, the software product of the research, computationally. All synthesized compounds were evaluated for cytotoxic effect against MDA-MB231 triple-negative breast cancer cell line by using WST-1 Cell Viability and Proliferation assay. Doxorubicin is in the anthracycline class and is an antineoplastic agent. It is used to provide regression in common neoplastic conditions such as breast carcinoma. Due to the cardiovascular side effects of doxorubicin, a combination study was conducted with the (& PLUSMN;)(R,S)-3-{1-[2-fluoro-(1,1 & PRIME;-biphenyl)-4-yl]ethyl}-4-methyl-5-{[2(trifluoromethyl)benzyl]thio}-4H-1,2,4-triazole (5l) with promising cytotoxic effects. As a result of the combination, it was shown as 7% MDA-MB231 cell viability. Therefore, based on the evaluations, a better cytotoxic effect was achieved with the 5l combination depending on the low dose of doxorubicin.
Citation Count: 3
Synthesis, in vitro and in silico studies on novel 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of mPGES-1
(Elsevier, 2023) Yelekçi, Kemal; Çiftçi, Gamze; Zhan, Chang-Guo; Ciftci, Gamze; Yelekci, Kemal; Duracik, Merve; Ozakpinar, Ozlem Bingol
Human microsomal prostaglandin E synthase (mPGES)-1 is a glutathione-dependent membrane-bound enzyme which is involved in the terminal stage of prostaglandin E2 (PGE2) synthesis. It has been well reported as a key target for the discovery of new anti-inflammatory and anti-cancer drugs. Specific in-hibitors of mPGES-1 are anticipated to selectively restrain the generation of PGE2 induced by the in-flammatory stimuli, without obstructing of the regular biosynthesis of other homeostatic prostanoids. Therefore, the design of mPGES-1 inhibitors can represent a better choice to take control of PGE2 asso-ciated diseases, compared with conventional non-steroidal anti-inflammatory drugs and cyclooxygenase (COX) inhibitors, which are known for their serious side effects. Although there is an intensive effort for the identification of mPGES-1 inhibitors, none of the unveiled molecules so far have reached the clini-cal market. Therefore, the development of novel mPGES-1 inhibitors with proper drug-like properties is still an unmet medical need. As a continuation of our research for the identification of new chemotypes which might inhibit this enzyme, we now report the design and synthesis of 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as inhibitors of human mPGES-1. All syn-thesized compounds were characterized by FTIR, 1 H NMR, 13 C NMR (for compounds 12, 14, 15, 26, 27) , HMBC (for compounds 6, 7, 8, 16, 19, 23, 28), and MS data. Twenty-four target compounds 7-30 were screened for their mPGES-1/COX-2 inhibitory activities as well as their cytotoxicity. Of these compounds, 20 and 24 showed potent mPGES-1 inhibition by IC50 values of 0.224 +/- 0.070 mu M and 1.08 +/- 0.35 mu M, re-spectively. These two compounds have also been observed to inhibit angiogenesis in matrigel tube forma-tion assay with no toxicity toward HUVEC cells. In silico studies were also held to understand inhibition mechanisms of the most active compounds using molecular docking, molecular dynamics calculations and ADMET predictions.(c) 2022 Elsevier B.V. All rights reserved.