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Öğe 1Kırıkkale Üniversitesi, Eğitim Fakültesi, Matematik ve Fen Bilimleri Eğitimi Bölümü, Kırıkkale, Türkiye 2İstanbul Gelişim Üniversitesi, Sağlık Bilimleri Yüksekokulu, 34315 Avcılar, İstanbul, Türkiye 3Gen Mühendisliği ve Biyoteknoloji Enstitüsü, Tübitak MAM, 41470, Gebze, Kocaeli, Türkiye(2017) Ökten, Salih; Çakmak, Osman; Tekin, ŞabanAmaç: Bu çalışmada, 6,8-disübstitüe kinolin türevlerinin antikanser potansiyelleri, etki mekanizmaları ve farklı sübstituentlerin aktiviteye etkilerinin belirlemesi amaçlanmıştır.Gereç ve Yöntem: Tetrahidrokinolin molekülü (1), moleküler brom (Br2) ile reaksiyonu ve müteakiben aromatlaştırılması ile 6,8-dibromo-1,2,3,4-tetrahidrokinolin (6,8-dibromoTHQ, 2) ve 6,8-dibromokinolin (6,8-diBrQ, 3) elde edildi. Bu moleküller, yer değiştirme ve Suzuki Kenetleme reaksiyonları sonucu ile 6,8-dimetoksikinolin (6,8-diMeOQ, 4), 6,8-disiyanokinolin (6,8-diCNQ, 6) ve 6,8-difenilkinolin'e (6,8-diPhQ, 5) dönüştürüldü. Sentezlenen bileşiklerin antikanser potansiyellerinin ortaya çıkartmak için HeLa (İnsan rahim kanser hücresi), HT29 (Kolon kanseri) ve C6 (Sıçan beyin kanser hücresi) hücre hatlarına karşı BrDU hücre proliferasyonu, LDH sitotoksisite, DNA bantlaşma ve DNA Topoizomeraz I inhibisyon testleri uygulandı.Bulgular: HT29 hücre hatlarında ise, bileşikler 2, 3, 4 ve 5 numaralı bileşikler hücre proliferasyonunu inhibe etmiştir fakat HeLa ve C6 hücre hatlarında sadece 6,8-dibromoTHQ 2 ve 6,8-diPhQ 5 bileşikleri önemli derecede antiproliferatif etki göstermiştir. 6,8-dibromoTHQ 2, tüm hücre hatlarında yüksek inhibisyon gösterirken, sitotoksik etki göstermemiştir. 6,8-dibromoTHQ 2 DNA bantlaştırma ve Topoizomeraz I enziminin inhibe edebilme özelliği ortaya çıkarılmıştır.Sonuçlar: Kinolin halkasının C-6 ve C-8 konumlarında fonksiyonel grupların değiştikçe farklı aktiviteleri gözlenmiştir. 6,8-DiBrTHQ 2 ve 6,8-diPhQ 5 moleküllerinin antiproliferatif ve apoptotik aktivite göstermeleri sebebiyle antikanser ajan olma potansiyelleri belirlenmiştirÖğe 6,8-disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması(2017) Ökten, Salih; Çakmak, Osman; Tekin, ŞabanAmaç: Bu çalışmada, 6,8-disübstitüe kinolin türevlerinin antikanser potansiyelleri, etki mekanizmaları ve farklı sübstituentlerin aktiviteye etkilerinin belirlemesi amaçlanmıştır.Gereç ve Yöntem: Tetrahidrokinolin molekülü (1), moleküler brom (Br2) ile reaksiyonu ve müteakiben aromatlaştırılması ile 6,8-dibromo-1,2,3,4-tetrahidrokinolin (6,8-dibromoTHQ, 2) ve 6,8-dibromokinolin (6,8-diBrQ, 3) elde edildi. Bu moleküller, yer değiştirme ve Suzuki Kenetleme reaksiyonları sonucu ile 6,8-dimetoksikinolin (6,8-diMeOQ, 4), 6,8-disiyanokinolin (6,8-diCNQ, 6) ve 6,8-difenilkinolin'e (6,8-diPhQ, 5) dönüştürüldü. Sentezlenen bileşiklerin antikanser potansiyellerinin ortaya çıkartmak için HeLa (İnsan rahim kanser hücresi), HT29 (Kolon kanseri) ve C6 (Sıçan beyin kanser hücresi) hücre hatlarına karşı BrDU hücre proliferasyonu, LDH sitotoksisite, DNA bantlaşma ve DNA Topoizomeraz I inhibisyon testleri uygulandı.Bulgular: HT29 hücre hatlarında ise, bileşikler 2, 3, 4 ve 5 numaralı bileşikler hücre proliferasyonunu inhibe etmiştir fakat HeLa ve C6 hücre hatlarında sadece 6,8-dibromoTHQ 2 ve 6,8-diPhQ 5 bileşikleri önemli derecede antiproliferatif etki göstermiştir. 6,8-dibromoTHQ 2, tüm hücre hatlarında yüksek inhibisyon gösterirken, sitotoksik etki göstermemiştir. 6,8-dibromoTHQ 2 DNA bantlaştırma ve Topoizomeraz I enziminin inhibe edebilme özelliği ortaya çıkarılmıştır.Sonuçlar: Kinolin halkasının C-6 ve C-8 konumlarında fonksiyonel grupların değiştikçe farklı aktiviteleri gözlenmiştir. 6,8-DiBrTHQ 2 ve 6,8-diPhQ 5 moleküllerinin antiproliferatif ve apoptotik aktivite göstermeleri sebebiyle antikanser ajan olma potansiyelleri belirlenmiştirÖğe Activation of 6-bromoquinoline by nitration: synthesis of morpholinyl and piperazinyl quinolines(Arkat Usa Inc, 2018) Çakmak, Osman; Ökten, Salih; Alimli, Dilek; Saddiqa, Aisha; Ersanlı, Cem CüneytQuinoline forms the key skeletal component of a number of important natural products and pharmacologically-active compounds. Despite a tremendous amount of research pertaining to the derivatization of quinoline, very few general synthetic routes are described in the literature starting from quinoline or tetrahydroquinoline. A simple and convenient method for the polyfunctionalization of quinolines via nitration of bromoquinolines has been developed. This method represents a new synthetic approach to convert brominated nitroquinoline derivatives into useful cyclic amines via nucleophilic-substitution (SNAr) reaction. [GRAPHICS] .Öğe Arylated Quinoline and Tetrahydroquinolines: Synthesis, Characterization and Their Metabolic Enzyme Inhibitory and Antimicrobial Activities(Wiley-V C H Verlag Gmbh, 2022) Kocyigit, Ümit Muhammet; Ökten, Salih; Çakmak, Osman; Burhan, Gizem; Ataş, Mehmet; Taslimi, Parham; Gülçin, İlhamiThe aims of this study are to synthesize and characterize some new phenyl quinoline derivatives and to determine the activities of them and the recently prepared substituted phenyl quinolines against Acetylcholinesterase (AChE) and Charbonic anyhydrase (CA) enzymes and some microorganisms. The 6-phenyl- (3a) and 6,8-diphenyl-(4a) tetrahydroquinolines were prepared by treatment of 6-bromo and 6,8-dibromo-1,2,3,4-tetrahydroquinoline with phenylboronic acids in the presence of Pd catalyze in high yields with respect to our reported procedure. Then, bromination of the 6-phenyl- (3a) and 6,8-diphenyl-(4a) tetrahydroquinolines furnished novel 3-bromo phenyl substituted quinolines 14 and 11 and 8-bromo-6-pheyltetrahydroquinoline (13) in excellent yields (91, 99 and 92 %, respectively). Structures of all prepared compounds were characterized by H-1 NMR,C-13 NMR, FTIR spectroscopy and elemental analysis. Both novel prepared and recent synthesized phenyl substituted tetrahydroquinolines and quinolines were screened for human carbonic anhydrase I, II isoenzymes (hCAs I and II) and AChE inhibitory and antimicrobial activities. Results indicated that all the synthetic compounds exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. K-i values of novel substituted (trifluoromethoxy, thiomethyl and methoxy) phenyl quinolines 3a-d, 4a-c, 8-12, and 14 for hCA I, hCA II and AChE enzymes were obtained in the ranges 0.31-12.44, 0.92-12.45, and 8.56-27.05 mu M, respectively. Moreover, phenyl quinolines 3a-b, 10, 11, 14 displayed antifungal effect against yeasts in the range of 125-15.62 mu g/mL.Öğe Biological activity and molecular docking studies of some new quinolines as potent anticancer agents(Humana Press Inc, 2021) Köprülü, Tuğba Kul; Ökten, Salih; Atalay, Vildan Enisoglu; Tekin, Şaban; Çakmak, OsmanThe objective of this study is to investigate the antiproliferative and cytotoxic properties and the action mechanism of substituted quinoline and tetrahydroquinolines 3, 4, 5, 7, and 8 against rat glioblastoma (C6), human cervical cancer (HeLa), human adenocarcinoma (HT29) cancer cell lines by BrdU Cell Proliferation ELISA, Lactate Dehydrogenase, DNA laddering and Topoisomerase I assays. The results of the study showed that 6,8-dibromotetrahydroquinoline 3 possess in vitro antiproliferative activity against C6, HeLa, and HT29 cell lines while morpholine/piperazine substituted quinoline 7 and 8 showed selective antiproliferative activity on C6 cell line with IC50 values 47.5 and 46.3 mu g/mL, respectively. Moreover, 6,8-dibromoTHQ 3 caused DNA fragmentation while it did not inhibit the Topoisomerase I (Topo I) enzyme. On the other hand, compound 8 did not cause DNA laddering while 8 inhibited the Topo I enzyme. According to these results, 6,8-dibromoTHQ 3 stimulates apoptosis on the C6 cell line while 6,8-dibromo-3-morhonilylquinoline (8) inhibits the Topo I enzyme to cause antiproliferative activity. Graphic abstractÖğe Biological evaluation of some quinoline derivatives with different functional groups as anticancer agents(Wiley, 2019) Köprülü, Tuğba Kul; Ökten, Salih; Tekin, Şaban; Çakmak, OsmanDue to a great deal of biological activities, quinoline derivatives have drawn attention for synthesis and biological activities in the search for new anticancer drug development. In this work, a variety of substituted (phenyl, nitro, cyano, N-oxide, and methoxy) quinoline derivatives (3-13) were tested in vitro for their biological activity against cancer cell lines, including rat glioblastoma (C6), human cervical cancer cells (HeLa), and human adenocarcinoma (HT29). 6-Bromo-5-nitroquinoline (4), and 6,8-diphenylquinoline (compound 13) showed the greatest antiproliferative activity as compared with the reference drug, 5-fluorouracil (5-FU), while the other compounds showed low antiproliferative activity. 6-Bromo-5-nitroquinoline (4) possesses lower cytotoxic activity than 5-FU in HT29 cell line. Due to its the apoptotic activity 6-Bromo-5-nitroquinoline (4) has the potential to cause cancer cell death.Öğe Quinoline-based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors(WILEY-V C H VERLAG GMBH, 2020) Ökten, Salih; Aydın, Ali; Koçyiğit, Ümit M.; Çakmak, Osman; Erkan, Sultan; Andaç, Cenk A.; Taslimi, ParhamA series of substituted quinolines was screened for their antiproliferative, cytotoxic, antibacterial activities, DNA/protein binding affinity, and anticholinergic properties by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation, lactate dehydrogenase cytotoxicity, and microdilution assays, the Wolfe-Shimmer equality method, the Ellman method, and the esterase assay, respectively. The results of the cytotoxic and anticancer activities of the compounds displayed that 6-bromotetrahydroquinoline (2), 6,8-dibromotetrahydroquinoline (3), 8-bromo-6-cyanoquinoline (10), 5-bromo-6,8-dimethoxyquinoline (12), the novelN-nitrated 6,8-dimethoxyquinoline (13), and 5,7-dibromo-8-hydroxyquinoline (17) showed a significant antiproliferative potency against the A549, HeLa, HT29, Hep3B, and MCF7 cancer cell lines (IC50 = 2-50 mu g/ml) and low cytotoxicity (similar to 7-35%) as the controls, 5-fluorouracil and cisplatin. The compound-DNA linkages are hyperchromic or hypochromic, causing variations in their spectra. This situation shows that they can be bound to DNA with the groove-binding mode, withK(b)value in the range of 2.0 x 10(3)-2.2 x 10(5) M-1. Studies on human Gram(+) and Gram(-) pathogenic bacteria showed that the substituted quinolines exhibited selective antimicrobial activities with MIC values of 62.50-250 mu g/ml. All tested quinoline derivatives were found to be effective inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase I and II isoforms (hCA I and II), withK(i)values of 46.04-956.82 nM for hCA I, 54.95-976.93 nM for hCA II, and 5.51-155.22 nM for AChE. As a result, the preliminary data showed that substituted quinolines displayed effective pharmacological features. Molecular docking studies were performed to investigate the binding modes and interaction energies for compounds2-17with AChE (PDB ID: 4EY6), hCA I (PDB ID: 1BMZ), and hCA II (PDB ID: 2ABE).Öğe Regioselective bromination: Synthesis of brominated methoxyquinolines(Pergamon-Elsevier Science Ltd, 2017) Çakmak, Osman; Ökten, SalihSimple synthetic methods are described for the synthesis of valuable polyfunctional brominated methoxyquinolines 10-13, 20-21, and 24-25. Three regioselective routes are described for convenient preparation of brominated methoxyquinolines at the C-2, C-3, and C-5 positions with consecutive reaction steps under mild reaction conditions using molecular bromine. While bromination of 6-bromo-8methoxy-1,2,3,4-tetrahydroquinoline (8) selectively gave 3,6-dibromo-8-methoxyquinoline (10) and 3,5,6-tribromo-8-methoxyquinoline (11), the reaction of 6,8-dimethoxy-1,2,3,4-tetrahydroquinoline (9) resulted in the formation of 3-bromo-6,8-dimethoxyqinoline (12) and tribromide 13. On the other hand, direct bromination of 6-methoxy- 17 and 6,8-dimethoxyquinoline (19) gave 5-bromo derivatives 20 and 21. However, the reaction 3,6-dimethoxyquinoline (8) resulted in dibromination to form 2,5dibromoquinoline (24). This process selectively led to functionalization of the quinoline ring at both the C-2 and C-5 positions. (C)2017 Elsevier Ltd. All rights reserved.Öğe Structural Characterization of 6-Bromo-5-nitroquinoline-1-oxide: A Quantum Chemical Study and XRD Investigations(2018) Ökten, Salih; Ersanlı, Cem Cüneyt; Çakmak, OsmanThe chemical properties of recently synthesized 6-bromo-5-nitroquinoline-1-oxide under a mild reaction condition by regioselective nitration of 6-bromoquinoline-1-oxide at C5 on going our research were investigated as theoretical. The crystal structure of 6-bromo-5-nitroquinoline-1-oxide, C9H5BrN2O3, was determined by X-ray analysis. Crystallized in Pmc21 in the orthorhombic space group with a 13.6694 (13) Å, b 9.6036 (10) Å, c 14.1177 (16) Å, Z 8, Dx 1.929 mg/m3. In this study, theoretical calculations were performed using the GaussView 4.1 molecular imaging program and the Gaussian03W packet program. In the ground state, stable structures of the wholes molecule in the gaseous phase are investigated based on Density Functional Theory (DFT). Molecularly optimized geometries, dipole moments, charge density, thermodynamic properties (heat capacity, enthalpy, entropy), chemical shift values (1H NMR and 13C NMR), energies, molecular electrostatic potentials and frontier orbitals (HOMO and LUMO) B3LYP/6-311G(d,p) base set. Thus, the results obtained by the X-ray diffraction method are supported by theoretical foundations. Finally, the distribution of interactions between molecules in the crystal structure of 6-bromo-5-nitroquinoline-1-oxide (3) was investigated by analysis using Hirshfeld surface production and two-dimensional fingerprinting.Öğe Yapı Aktivite İlişkisi (SAR): Bromlanmış 8-hidroksikinolin ve ftalonitril türevlerinin çeşitli kanser hücre hatları üzerine antiproliferatif aktivitelerinin incelenmesi(2017) Ökten, Salih; Köprülü, Tuğba Kul; Çakmak, Osman; Tekin, ŞabanBu çalışmada, 8-hidroksikinolin’den ftalonitriller 6, 7 ve bunların bromlu türevleri 8, 9 sentezlenerek bu moleküllerin C6 (sıçan glial tümör), HeLa (insan rahim ağzı kanser hücresi) ve HT29 (insan adenokarsinoma) kanser hücre hatları üzerindeki antiproliferatif ve sitotoksik aktiviteleri araştırılmıştır. 7- Bromo- ve 5,7-dibromo-8-hidroksikinolin türevleri (2 ve 3) ile ftalonitril 6, 7 ve bunların bromlu türevleri 8, 9 antiproliferatif ve apoptotik etkileri yapı aktivite ilişkisi (SAR) yönüyle karşılaştırılmıştır. Bromohidroksikinolin 2 ve 3 türevleri, literatür kayıtlarına göre yüksek antiproliferatif aktivite göstermesine rağmen, 8-hidroksikinolinden hazırlanan ftalonitril bileşikleri 6, 7 ve bromlanan 8, 9 türevlerinin antiproliferatif aktiviteyi belirgin bir biçimde azalttığı belirlenmiştir. Kinolin çekirdeğinin C-8 konumundaki yapı aktivite çalışması, antiproliferatif ve apoptotik aktivitenin OH grubunun sebep olduğu ortaya çıkartmıştır. Ayrıca kinolin halkasının OH grubuna alkil ya da sübstitüe halkalı grupların bağlanması ve bromlanması da antiproliferatif aktiviteyi düşürmüştür.
