Sürdürülebilir Kalkınma Amaçları
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- ArticleYalnız künye2023Novel Pyrazole-Based Benzofuran Derivatives as Anticancer Agents: Synthesis, Biological Evaluation, and Molecular Docking Investigations
Ameziane El Hassani, Issam; Altay, Ahmet; Karrouchi, Khalid; Yeniçeri, Esma; Türkmenoğlu, Burçin; Assila, Hamza; Boukharssa, Youness; Ramli, Youssef; Ansar, M'hammed
In this work, the design, synthesis, and mechanistic studies of novel pyrazole-based benzofuran derivatives 1–8 as anticancer agents were discussed. Cytotoxic potency of the title compounds was evaluated against the lung carcinoma A-549, human-derived colorectal adenocarcinoma HT-29, breast adenocarcinoma MCF-7 cells as well as mouse fibroblast 3T3-L1 cells using XTT assay. Anticancer mechanistic studies were carried out with flow cytometry. XTT results revealed that all compounds exhibited dose-dependent anti-proliferative activity against the tested cancer cells, and especially compound 2 showed the strongest anti-proliferative activity with an IC50 value of 7.31 μM and the highest selectivity (15.74) on MCF-7 cells. Flow cytometry results confirmed that the cytotoxic power of compound 2 on MCF-7 cells is closely related to mitochondrial membrane damage, caspase activation, and apoptosis orientation. Finally, molecular docking studies were applied to determine the interactions between compound 2 and caspase-3 via in-silico approaches. By molecular docking studies, free binding energy (ΔGBind), docking score, Glide score values as well as amino acid residues in the active binding site were determined. Consequently, these results constitute preliminary data for in vivo anticancer studies and have the potential as a chemotherapeutic agent.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim20224D-QSAR Analysis of Some New Pyrrole Derivatives Using Klopman Index Descriptor
Türkmenoğlu, Burçin; Güzel, Yahya; Kızılcan, Dilek Şeyma; Aslan, Ertuğrul
We applied the Klopman Index, the Local Reactive Descriptor (LRD), for 3-Dimensional (3D) interactions between the Ligand-Receptor (L-R), for some new pyrrole derivatives as antituberculosis agents for 4-Dimensional Quantitative Structure-Activity Relationship (4D-QSAR) investigations. The parameters of the receptor side belonging to the Pharmacophore (Pha), which consists of the interaction points suggested between L-R, were calculated in the Molecular Conformer Electron Topological (MCET) method we developed based on the LRD values on the ligand side. After the 4D-QSAR model was established with the Leave One Out Cross-Validation (LOO-CV) technique on the molecules in the training set, the model was confirmed on the molecules in the external test set. Statistical results obtained from both sets, Q2 = 0.875 and Rext2 = 0.918, respectively, were evaluated as satisfactory.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Synthesis of (p-tolyl)-3(2H)pyridazinone Derivatives as Novel Acetylcholinesterase Inhibitors
Merde, İrem Bozbey; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra; Özçelik, Azime Berna; Uysal, Mehtap
In this study, a series of N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a–m) were confirmed by 1H-NMR, 13C-NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives inhibited the enzymes significantly. Ki values for acetylcholinesterase in the range of 0.56±0.15–4.12±1.42 μM. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56±0.15 μM). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in-vitro. As a result of molecular docking studies (ΔGBind, docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Conventional and microwave prompted synthesis of aryl(alkyl)azole oximes, 1H-NMR spectroscopic determination of E/Z isomer ratio and HOMO-LUMO analysis
Bozbey, Irem; Uslu, Harun; Türkmenoğlu, Burçin; Özdemir, Zeynep; Karakurt, Arzu; Levent, Serkan
In this study, 12 oxime derivatives were synthesized by using with conventional method and microwave irradiation method. It was aimed to compare the effectiveness of the conventional method and microwave method. Their yields were determined for both methods, and the yields increased when the microwave method was used. The compounds which have oxime show geometric isomerism because they have carbon-nitrogen double bonds. Therefore, we have also aimed to evaluate their E/Z isomer ratios in this study. While the synthesized pyrazole derivative compounds were mostly obtained in Z isomer in both synthesis methods, it was observed that some of the title compounds were almost completely obtained as E isomers when the conventional synthesis method was used in the synthesized imidazole derivative compounds. The structures of synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR and HRMS spectra. Additionally, in this study, the HOMO-LUMO energies and thermodynamic properties of the E/Z isomers of 12 oxime derivatives were performed using the 6-31 * G basis set and the Density Functional Theory (DFT) calculation using the B3LYP method three different environments (water, ethanol, vacuum). In addition, geometric parameters such as chemical hardness (η), chemical potential (µ), electrophilicity index (ω), chemical softness (σ) were calculated depending on the calculated HOMO-LUMO energies.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Comparison of the performance of different “local reactive descriptors” in 3D-QSAR analysis of enantioselective molecules
Kızılcan, Dilek Şeyma; Türkmenoğlu, Burçin; Güzel, Yahya
The interaction between Ligand-Receptor (L-R) to solve the pharmacological and toxicological problems of enantioselective molecules was studied as 3D Quantitative Structure-Activity Relationship (3D-QSAR). The biological activity of enantiomers of stereo isomeric molecules that differ in 3D can only be determined by the Local Reactive Descriptor (LRD). The parameters of the Pharmacophore (Pha) on the receptor side can be determined using LRDs of atoms of the molecule in 3D space. “Klopman index,” which was brought to the literature as LRD by us, was compared with typical LRD descriptors such as atom charge, Fukui index, frontier orbital coefficients (HOMO/LUMO) in our Molecular Conformer Electron Topological (MCET) program. After predicting the 3D-QSAR model with the Leave One Out-Cross Validation (LOO-CV) technique on the molecules in the training set, the model was validated on the molecules in the external test set. Statistical results from both sets were evaluated for all LRDs, and the best results were obtained as Q2 = 0.955 and R2= 0.964 in the Klopman index.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Investigation of novel compounds via in silico approaches of EGFR inhibitors as anticancer agents
Türkmenoğlu, Burçin
Before the experimental studies of a compound to be synthesized from in vitro to in vivo, it is possible to save both time and money with in silico approaches only with Computer Aided Drug Design (CADD) methods. In other words, compounds that can be new drug candidates can be suggested by drug design using computational drug discovery strategies. In this study, all molecules in the ChEMBL Database were virtual screened based on drugs with inhibitory properties on the Epidermal Growth Factor Receptor (EGFR), one of the receptor tyrosine kinases, which is effective in cancer cells. During this High-Throughput Screening (HTS), the number of compounds was minimized according to the parameters of the reference drugs, physicochemical properties such as logP, M.W., HBA, HDB, RosLip. As a result of in silico approaches and molecular docking analysis, ten compounds with the highest docking scores were determined and a model compound that could be a new drug candidate was proposed.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Dicyanoargentate(I)-based complexes induced in vivo tumor inhibition by activating apoptosis-related pathways
Aydın, Ali; Korkmaz, Nesrin; Kısa, Dursun; Türkmenoğlu, Burçin; Karadağ, Ahmet
Colorectal adenocarcinoma, which often occurs as a result of a typical chromosomal instability and mismatch repair deficiencies resulting in resistance to apoptosis, is a significant burden on society. Previously, we demonstrated strong apoptosis triggers Ag(I) complexes in vitro, including [Ni (hydeten)2Ag(CN)2] [Ag (CN2].H2O (C1), [Ni (bishydeten)2] [Ag (CN)2]2.H2O (C2), and [Ni(N-bishydeten)Ag3(CN)5] (C3), which specifically induce the apoptotic mechanism of cancer cells and selectively is non-cytotoxic within normal cells. Herein, we introduce in vivo the ability of Ag(I) complexes to activate apoptosis and interact with cell cycle and cell fate-related proteins. To assess antitumor efficacy, we evaluated tumor volume, survival rate, and protein status related to cell cycle, apoptosis, and oxidative stress (by immunohistochemistry, genetic expression, and ELISA assays). In addition, in this study, using molecular docking study, the interactions of metal complexes on many proteins were examined, and the findings related to their theoretical anticancer activities were obtained and compared. The in vivo evaluation of Ag(I) complexes (10 mg/kg) against HT29 xenograft tumor model in the CD1 nude and BALB/c mice revealed a remarkable decrease in the tumor volume and increase survival rate. The weight-loss situation and histopathological indicators of Ag(I) complexes-treated mice approved that the Ag(I) complexes have a considerable healing effect on solid tumors with negligible side-effect on the tissue. This promising information strongly expresses that Ag(I) complexes may fulfill the task of an antitumor agent and be a potential candidate for a chemotherapeutic approach against colorectal adenocarcinoma.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Investigation of Nirmatrelvir with Different Crystal Structures Effective on SARS-CoV-2 by In Silico Approaches
Türkmenoğlu, Burçin
A pandemic has been declared in the world with the Covid-19 disease caused by the SARS-CoV-2 virus. Scientists on this disease, which is of antiviral origin, have been seeking treatment against SARS-CoV-2 with experimental and computational methods since December 2019. Nirmatrelvir (PF-07321332; NMV), the antiviral component of PAXLOVID™, has been introduced as an inhibitor of the main protease (MPro) of this disease, which is a threat to human health, SARS-CoV-2. By analyzing the binding interactions between the target and the ligand as in silico with the molecular docking method of Computer Aided Drug Design (CADD), parameters such as amino acids in the binding site, docking score values, binding energy values can be determined. In this study, to six different binding parameters (Docking score, XP GScore, Glide evdw, Glide energy, Glide emodel, MM-GBSA ΔGBind) of Nirmatelvir, an orally taken drug, on the effective crystal structures (7O46, 7QBB, 7NEO, 7B77, 7B2U, 7B2J, 7NBT and 7TVX) of MPro in SARS-CoV-2, were investigated with Schrödinger 2021-2 (Schrödinger, LLC New York, ABD) software. It is presented in this study that different crystal structures have different interactions.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022A bis indole analog molecule fluorescent probe for living cell staining
Beşer, Burcu Meryem; Altay, Ahmet; Talaz, Oktay; Türkmenoğlu, Burçin
In this study, the fluorescent probe property of a bis indole compound (5,14-dimethyl-5,6,7,8,9,14-hexahydroindolo [2 ', 3′: 3,4] cycloocta [1,2-b] indole), a Caulerpin derivative, which is a member of the indole family, was investigated. For this purpose, firstly, the fluorescence character of the molecule was investigated by absorption and fluorescence spectroscopy techniques in both solvent and surfactant environments. Afterwards, the cytotoxicity of the molecule was tested on the human colon cancer HT-29 cells and breast cancer MCF-7 cells as well as mouse fibroblast 3T3-L1 cells. After determining that the molecule has no cytotoxic effect against all the tested cell lines by 100 µM, the cell staining feature of the probe was examined. The obtained data showed us that the molecule, whose confocal microscopy images were taken at 360 nm excitation wavelength, stained the cell cytoplasm. In addition, optical absorption spectra, oscillator strength (f), transition configuration and transition characteristics of the Ars-In in different solvents were investigated at the theoretical level using Time Dependent-Density Functional Theory (TD-DFT). In conclusion, these results confirm that this indole derivative molecule could be evaluated as an effective fluorescence probe for biological systems.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022A New Schiff Base Molecule Prepared from Pyrimidine-2-thione: Synthesis, Spectral Characterization, Cytotoxic Activity, DFT, and Molecular Docking Studies; [Pirimidin-2-tiyondan Hazırlanan Yeni Bir Schiff Bazı Molekülü: Sentez, Spektral Karakterizasyon, Sitotoksik Aktivite, DFT ve Moleküler Doking Çalışmaları]
Kökbudak, Zülbiye; Türkmenoğlu, Burçin; Akkoç, Senem
Schiff base derivatives are some of the most widely used organic compounds for industrial purposes and they exhibit a broad range of biological activities. In this paper, a new Schiff base derivative (2) synthesized from the condensation reaction of 1-amino-5-benzoyl)-4-phenylpyrimidine-2(1H)-thione (1) with 2-chlorobenzaldehyde. The new compound was characterized by1 H,13 C NMR, and FT-IR. The biological activity property of this compound was tested against two different cancer cell lines and a healthy human cell line. The results demonstrate that molecule 2 has antiproliferative activity. In molecular modeling studies, the interaction site was examined using the epidermal growth factor receptor (EGFR) tyrosine kinase domain. Alignment in molecular docking, surface mapping binding, amino acids, and binding energy calculated. Glide score energy was found to be-9.820 kcal/mol and it predicted that the bonding interaction is strong. Theoretical calculations were made to compare the experimental and theoretical data. These calculations were performed on the 6–31 G* basis set using the Density Functional Theory (DFT) method and Becke-3-Parameter-Lee-Yang-Parr (B3LYP). Using this method, various parameters, such as frontier molecular orbitals, HOMO-LUMO energy levels, band gap, and chemical reactivity indices were found and interpreted.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022(p-Chlorophenyl)-3(2H)pyridazinone Derivatives: Synthesis, in Silico, and AChE/BChE Inhibitory Activity
BozbeyMerde, İrem; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra
A series of novel (p-chlorophenyl)-3(2H)pyridazinone compounds were synthesized starting from p-chloroacetophenone as AChE/BChE inhibitors. The chemical structures of all the compounds were identified by spectral analysis. Cholinesterase inhibition activity studies and in silico studies of compounds designed to eliminate the symptomatic effects of Alzheimer's disease and slow down neurodegeneration were evaluated. According to the results obtained, it was revealed that N-substituted-(p- chlorophenyl)pyridazin-3(2H)-one derivatives inhibited enzymes significantly. Ki values were found for acetylcholinesterase in the range of 10.2±4.0–20.9±7.6 nM and for butyrylcholinesterase in the range of 0.70±0.34–1.67±1.12 nM. Compound 5e showed the best effect on AChE activity compared to Tacrine. Also, compound 5b showed the best effect in BChE inhibition. The interactions of the synthesized compounds with the best experimental activities against AChE, BChE, respectively, were investigated by in silico approaches. In molecular docking, 5b compound with AChE crystal structure (PDB ID:1ACJ), binding site and binding parameters of 5e compound with BChE crystal structure were investigated in detail. The results indicated that compound 5b and 5e could be a promising lead compound for further development as a therapeutic agent for Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye20223(2H)-pyridazinone derivatives: Synthesis, in-silico studies, structure-activity relationship and in-vitro evaluation for acetylcholinesterase enzyme inhibition
Çöl, Ömer Faruk; Bozbey, İrem; Türkmenoğlu, Burçin; Uysal, Mehtap
New ten compounds bearing pyridazinone ring (5a–j) were designed and synthesized as acetylcholinesterase inhibitors. The new derivatives were acquired via the reaction of propionohydrazides with substituted/nonsubstituted sulphonylchlorides. The structures of the synthesized compounds were explained using FT-IR, 1H-NMR, 13C-NMR, elemental analysis and HRMS spectra. The inhibition profiles of the synthesized compounds on AChE were researched by comparing their IC50 and KI values. According to the activity studies, all the compounds showed significant inhibitory activity against AChE relative to the reference compound Tacrine. The compound 5g showed the best acetylcholinesterase inhibitory effect with a KI value of 11.61 ± 0.77 nM. For all compounds, the parameters of the interaction points on the receptor side were determined on the ligand basis with the 4D-QSAR model. The synthesized pyridazinone derivatives, 5(a-j), were screened for their acetylcholinesterase inhibitory potential, and the results determined that among the series, compounds 5g, 5f and 5j showed the best inhibition, respectively. For anti-Alzheimer activities, 5g, 5f and 5j compounds were performed in silico studies to understand the binding site, binding energy properties in molecular docking.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Inhibitory effects of novel 3(2H)pyridazinone-triazole derivatives against acetylcholinesterase enzyme
Bozbey, İrem; Önel, Gülce Taşkor; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra; Ergün, Muhammed; Özçelik, Azime Berna; Uysal, Mehtap
Alzheimer's disease is a neurological disease characterized by the destruction of brain cells. In this disease, which causes a decrease in thought, memory and behavioral functions, the symptoms appear gradually with age. In this study, inhibition of acetylcholinesterase enzyme which is an important target in accordance with the cholinergic hypothesis, was studied. New 3(2H)pyridazinone-triazole derivatives were synthesized, confirmed by1H-NMR,13C-NMR, HRMS analysis and their IC50 and Ki values were studied. The inhibition constants (Ki) of the compounds against the AChE enzyme ranged from 2.35 ± 0.18 to 5.15 ± 0.46 µM. The compound with the best inhibitory properties was compound 6d with a Ki value of 2.35 ± 0.18 µM. In addition, to support the experimental data, molecular docking studies were carried out with 6b, 6d, 6e and 6f compounds with AChE crystal structure (PDB ID:4M0E).
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Design, synthesis, anticancer evaluation and molecular docking studies of new imidazo [2, 1-b] thiazole -based chalcones
Dadou, Said; Altay, Ahmet; Koudad, Mohammed; Türkmenoğlu, Burçin; Yeniçeri, Esma; Çağlar, Sema; Allali, Mustapha; Oussaid, Adyl; Benchat, Noureddine; Karrouchi, Khalid
A new series of imidazo[2, 1-b]thiazole-based chalcone derivatives were designed, synthesized, and tested for their anticancer activities. Firstly, the cytotoxic ability of the compounds was tested on three different types of cancer cells, namely colorectal adenocarcinoma (HT-29), lung carcinoma (A-549), breast adenocarcinoma (MCF-7), and mouse fibroblast cells (3T3-L1) by XTT tests. Afterwards, further anticancer activity studies with the compound 3j having the lowest IC50 and highest SI values were performed on MCF-7 cells. XTT results revealed that all the test compounds exhibited much higher cytotoxic activity on the cancer cells than that of normal 3T3-L1 cells. Among the compounds, 3j especially stood out with its IC50 (9.76 µM) and SI (14.99) values on MCF-7 cells. Flow cytometry analysis proved that 3j-treated MCF-7 cells was resulted in the mitochondrial membrane depolarization, multicaspase activation, and ultimately apoptosis. Additionally, in silico molecular docking approaches were carried out to confirm the experimental observations and investigate the efficacy of the compound 3j. The interactions of 3j on DNA dodecamer and caspase-3 were investigated by molecular docking studies. Based on these interactions, the active amino acids in the binding site were determined and their free binding energies (ΔGBind) were calculated.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2022Novel (p-Tolyl)-3(2H)-Pyridazinone Derivatives Containing Substituted-1,2,3-Triazole Moiety as New Anti-Alzheimer Agents: Synthesis, In vitro and In silico Assays; [1,2,3-Triazol Uygulaması Yeni Anti-Alzheimer (P-Tolil)-3(2H)-Piridazinon Türevleri: Sentez Çalışmaları, in vitro ve in siliko Analizleri]
Bozbey Merde, İrem; Taşkor Önel, Gülce; Türkmenoğlu, Burçin; Gürsoy, Şule; Di̇Lek, Esra
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is the most common cause of dementia. The risk of developing the disease increases with age. When the histopathology of the disease is examined, senile amyloid plaques, neurofibrillary tangle formation, synapse-neuron loss, and marked atrophy in the brain are detected. The decrease in the level of choline acetyltransferase, which is responsible for the synthesis of acetylcholine in Alzheimer’s disease, is 58-90%. There is a great need for new drugs that target the basis of the cause of the disease, as existing drugs cannot stop the progression of the disease. In this study, triazole-pyridazinone derivative compounds showing acetylcholinesterase inhibition were synthesized and their inhibitions were investigated. Compound 6e exhibited the strongest inhibitory effect with a Ki value of 0.049 ± 0.014 µM (Tacrine Ki= 0.226 ± 0.025 µM). In addition, in silico studies were applied for all compounds.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2022Pyridazinones containing the (4-methoxyphenyl)piperazine moiety as AChE/BChE inhibitors: design, synthesis, in silico and biological evaluation
Merde, İrem B.; Önel, Gülce T.; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra
Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting the elderly population accompanied by a decrease in cholinergic transmission, impairing cognitive functions. Acetylcholine deficiency is important in the development of disease symptoms. Inhibition of acetylcholinesterase, an important enzyme in acetylcholine hydrolysis, is one of the important drug targets to increase acetylcholine levels. In this study, we aimed to develop acetylcholinesterase inhibitor compounds. For this, we synthesized compounds 6(a–e) bearing 3(2H)-pyridazinone and 1,2,4-triazole ring structures. We determined the IC50, Ki and inhibition types of N-substituted-(p-methoxyphenyl)pyridazin-3(2H)-one derivatives that we synthesized and elucidated their structures. The compound with the best AChE activity was compound 6b (Ki = 3.73 ± 0.9 nM) with the p-methylphenyl group it carried and showed competitive inhibition. Kinetic study was also performed for the compounds with the highest BChE 6a (Ki = 0.95 ± 0.16 nM) inhibitory activities. Molecular docking studies have shown that the p-methylphenyl group is indeed active in the hinge region of the AChE crystal structure as a result of experimental activity. In addition, the best free binding energy (ΔGBind), docking score and Glide score values were determined by examining the interactions with AChE crystal structure for compound 6b and with BChE crystal structure for 6a in silico approaches. [Figure not available: see fulltext.]
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2021Confirmation by molecular docking of the pharmacophore defined as 4D-QSAR using the MCET method for the 2-hydroxydiarylamide derivatives
Türkmenoğlu, Burçin; Güzel, Yahya
For the 2-hydroxydiarylamide derivative series that inhibitsserine proteases by mediating various events related to the basicprocesses of tumor invasion and metastasis in cancer, thepharmacophore (Pha) responsible for the activity was estimatedby the Molecular Conformer Electron Topological (MCET)method. The atoms in the common core structure of themolecules and template are aligned so that the remainingoriented atoms superimposition with the maximum number.Pha; in the 4D-QSAR analysis, it is selected and used torepresent the molecule that can interact best by the receptoramong all conformers. The model proposed in the training setwas verified in the external test set and the electronicidentifying values of the Pha atoms in both sets wereconsidered. With Leave One Out-Cross Validation (LOO-CV)the model proposed according to 33 molecules in the trainingset (q2 = 0.998) was validated by using 8 molecules (r2 = 0.993)in the external test set. As a result of the MCET method, theproposed pharmacophore structure was confirmed usingmolecular docking
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies
Çağlar Yavuz, Sevtap; Akkoç, Senem; Türkmenoğlu, Burçin; Sarıpınar, Emin
In a single reaction step, pyrimidine derivatives (4a-p) were synthesized from the triple reaction of aromatic aldehydes (1), ethyl cyanoacetate (2), and some guanyl hydrazone derivatives (3a-n). These compounds were tested as in vitro against two types of cancerous cell lines, namely, a human colon cancerous cell line (DLD-1) and a human breast cancerous cell line (MDA-MB-231). According to the obtained results, nearly all the compounds have cytotoxic activity in the tested cell lines. Especially, the compounds 4j, 4k, and 4n had a significant effect against DLD-1. Furthermore, compounds 4g, 4m, and 4o exhibited lower IC50 values compared to other synthesized compounds against MDA-MB-231. We hope that these compounds can be improved as anticancer agents in the future. Molecular docking was performed according to both topoisomerase I and N-acetyltransferase 1 proteins to examine theoretically the binding mode and site of pyrimidine compounds having the best activity.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020The use of the Klopman index as a new descriptor for pharmacophore analysis on strong aromatase inhibitor flavonoids against estrogen-dependent breast cancer
Kızılcan, Dilek Şeyma; Türkmenoğlu, Burçin; Güzel, Yahya
We present the Klopman index, which is effective in explaining the mechanisms of organic chemistry, in quantitative structure activity relationship (QSAR) studies on flavonoids as a new descriptor for the first time. Instead of using random descriptors to elucidate the interactions between the ligand and the receptor, the atomic local reactive descriptor (LRD) which we call as the Klopman index in our molecular conformer electron topological (MCET) program was used. Both the atomic charges and the frontier orbital coefficients are used simultaneously in the Klopman index. Substrate-aromatase interactions of strong aromatase inhibitors against estrogen-dependent breast cancer were investigated by the pharmacophore model (PhaM) defined using MCET. All the conformers in the series were aligned with the template to match with the enzyme in three dimensional (3D). The parameters of the enzyme at the interaction points were determined according to the descriptor of the molecules in the training set. Contour maps of enzyme parameters show the interaction points of aromatase with the flavonoid group used in this study. Traditional validation parameters (Q2 = 0.883 and R2pred = 0.895) were supported by a more stringent validation (a new parameter R2m-overall = 0.6).
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2020Investigation of inhibitory activity of monoamine oxidase A with 4D-QSAR using Fukui indices identifier
Türkmenoğlu, Burçin; Güzel, Yahya; Su, Ekrem Mesut; Kızılcan, Dilek Şeyma
The inhibitory activity of monoamine oxidase A (MAO-A) was investigated as 4D- Quantitative Structure-Activity Relationship (4D-QSAR) using Molecular Conformer Electron Topological (MCET), a ligand-based method. The activity of MAO-A according to a 3D interaction was explained by a descriptor with the Fukui indices, which represents the hard-soft acid / base reactivity of atoms. The Fukui indices of atoms in clusters was used as the Local Reactive Descriptor (LRD) of the ligand side. Stochastic approaches were made for each sub-cluster proposed by the Genetic Algorithm (GA). The parameters at receptor side of pharmacophore (Pha) were calculated based on the Fukui indices used as descriptors on the ligand side. Pha was determined based on ligand of synthetic derivatives that are MAO-A inhibitors. Molecular conformers with the most suitable atoms with the template conformer can be selected as one of the most suitable spatial structures for interaction with the receptor. This serves to determine the LRD values of the atoms in the conformer Pha. Depending on the values of the descriptors of the ligand at the points of interaction, it may be either an activity-increasing auxiliary groups (AG) or anti-pharmacophore shielding groups (APS). The model was developed with Leave One Out-Cross Validation (LOO-CV), for the 24 molecules in the training set, and was validated for 8 molecules in the test set. Inhibitory activities determined from the established model were compared with experimental results. For the training set and the external cross validation test set compounds, the Q2 (0.829) and R2 (0.818) of the statistical parameters were calculated, respectively.
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