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Öğe Bromination and conversion of tetrahydro-1H-indene to bisoxirane with a new approach: synthesis, structural characterization by spectroscopic and theoretical methods, and biological analysis supported by DFT and docking(Tubitak Scientific & Technological Research Council Turkey, 2023) Yılmaz, Raşit Fikret; Erkan, Sultan; Ökten, Salih; Tutar, Ahmet; Şahin, ErtanIn this study, a new method for synthesizing diepoxides is proposed. Tetrahydroindene 1 was brominated with NBS in the presence of LiClO4 and acetic acid, resulting in the formation of dibromodiacetate derivatives 2 and 3. Treatment of compounds 2 and 3 with NaOH in methanol produced a mixture of diepoxides 4 and 5. Additionally, direct bromination of tetrahydro-1H-indene yielded tetrabromo octahydroindene isomers 6 and 7. The structures of the compounds were characterized using spectroscopic techniques such as H-1 NMR, C-13 NMR, APT, COSY, and XRD. The new method provides an easy and selective route to access epoxides for the synthesis of various chemicals. This study also highlights the selective formation of endo-exo and exo-exo orientations of the obtained diepoxides, distinguishing it from previous studies. The stability and properties of the stereoisomers were investigated using computational methods, revealing the most stable configurations. Reactive sites in the molecules were identified using contour diagrams and molecular electrostatic potential maps. The anticancer properties of the compounds were evaluated in silico, comparing them to 5-fluorouracil (5-FU) against several cancer cell lines. The compounds exhibited the most effective anticancer activity against MCF-7 cells, with the order of anticancer activities generally determined as 2 > 7 > 3 > 6 > 5 > 4 > 5-FU.Öğe Bromokamfenlerin Etkin Sentezi, Suzuki Kenetlenme ve Yer Değiştirme ReaksiyonlarıiIle Yeni Türevlerin Sentezi(2020) Tutar, Ahmet; Ökten, Salih; Yılmaz, Raşit Fikret; Islam, Md ZahıdulBu projede doğal bir bileşik olan kamfenin yer değiştirme ve Suzuki-Miyaura kenetlenme reaksiyonları ile biyoaktif özelliğe sahip yeni türevlerinin sentezlenmesi amaçlanmıştır. Kamfen türevlerinin sentezi için farklı metotlar geliştirilmiştir. Fakat kamfenin brominasyonu sırasında düzenlenme ürünlerinin oluşması ve reaksiyon verimlerinin düşük olması yeni türevlerin sentezini sınırlamıştır. Grubumuzdaki çalışmalarla, farklı reaksiyon şartları uygulanarak düzenleme durdurulmuş ve yeni kamfen türevlerinin sentezi için yeni bir metodoloji geliştirmiştir. Kenetlenme reaksiyonları ve yer değiştirme reaksiyonları da sentetik kimyada önemli temel reaksiyonlardır. Bu projede, kamfenbromürlerin farklı sübstitüentlerle yer değiştirme reaksiyonları ve farklı boronik asitlerle kenetlenme reaksiyonları incelenmiştir. Bu çalışma ile doğal bileşik olan kamfenin kenetlenme reaksiyonu ilk kez yapılarak yeni potansiyel biyoaktif bileşikler sentezlenmiştir. Hedeflenen bileşiklerin sentezlenmesinde aşağıdaki reaksiyon basamakları uygulanmıştır. (1) (-)-Kamfen ve (+)-kamfenden çıkılarak monobromokamfenler sentezlendi. Bu sentez aşamasında (-)-kamfen, 650 W ışıkta moleküler brom ile muamele edilerek dibromokamfen hazırlandı. Ardından THF içerisinde t-BuOK ile muamele edilerek monobromokamfen karışımı elde edildi. Bu karışıma gerekli saflaştırma işlemleri uygulanarak E- ve Zbromokamfen türevleri elde edildi. (2) E-bromokamfenin, 5 farklı boronik asit ile Suzuki- Miyaura kenetleme reaksiyonları yapıldı. Bu sentezde E-bromokamfen, katalitik miktarda Pd(OAc)2 varlığında toluen içerisinde kaynatıldı. Gerekli saflaştırma işlemlerinden sonra hedeflenen aril sübstitüe kamfen bileşikleri elde edildi. (3) E-bromokamfenin, yer değiştirme reaksiyonları yapıldı. Bu sentezde E-bromokamfen, ayrı ayrı CH3Ona ve CuCN ile DMF içerisinde etkileştirilerek metoksi ve siyano kamfen türevleri elde edildi. (4) Elde edilen bileşiklerin spektroskopik ölçümleri ve yapı analizleri incelenmiştir. Kamfen halkasında düzenlenmenin durdurulabildiği, brominasyon ile fonksiyonel hale getirilerek yeni moleküllerin sentezlenebileceği gösterilmiştir.Öğe Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper induced reactions(Pergamon-Elsevier Science Ltd, 2016) Ekiz, Makbule; Tutar, Ahmet; Okten, SalihThe bromination of 2-aminobenzonitrile (2) with molecular bromine (2 equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6,14-18) utilizing Friedlander reactions. A convenient route is described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6 and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)(3)Cl, S-2(Me)(2)]. Both were converted to the corresponding cyano derivatives (21-23) via copper-assisted nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in 25% yield. (C) 2016 Elsevier Ltd. All rights reserved.Öğe Determination of anticancer and antibacterial activities of disubstituted tacrine derivatives(2019) Ökten, Salih; Aydın, Ali; Tutar, AhmetThe present study describes the biological features of disubstituted tacrine derivatives using cell proliferation andcell cytotoxicity assays. The abilities of tacrine derivatives to inhibit microbial growth and to interact with DNA werealso investigated. Here, the tested compounds (1-4) exhibited selective antiproliferative activity against the cancercell lines (IC50 values 1.1 – 38.9 ?g/mL) and showed a similar non-toxic property to cells such as positive control(percent cytotoxicity 7% - 27%). Studies on human pathogenic bacteria showed that the novel tacrine analoguesexhibited significant antimicrobial activities between concentrations of 31.25 ?g/mL and 250 ?g/mL. The data showthat they can bind to DNA with the groove binding mode with Kb range of 7.4 10? - 2.9 10? M?¹. As a result, thepreliminary data showed that disubstituted tacrine derivatives exhibited effective pharmacological properties.Öğe In-Vitro Anticancer and Antibacterial Activities of Brominated Indeno[1,2-b]qinoline Amines Supported with Molecular Docking and MCDM**(Wiley-V C H Verlag Gmbh, 2021) Aydin, Ali; Okten, Salih; Erkan, Sultan; Bulut, Merve; Ozcan, Evrencan; Tutar, Ahmet; Eren, TamerThe present study describes mono substituted indeno[1,2-b]quinolines (3 a-c and 5) have much more antiproliferative potentials than positive controls against A549, HeLa, MCF7 and Hep3B cell lines (IC50 values 1.1-29.6 mu g/mL) and show similar cytotoxicity (14.3 % to 19.8 %) to cells such as controls. Moreover, the mono substituted indeno[1,2-b]quinoline amines (3 a-c and 5) exhibit significant antimicrobial activity with MIC values between 15.62 mu g/mL and 250 mu g/mL. The compounds can also bind to DNA in the groove binding mode with a binding constant range of 1.1x10(3)-1.1x10(5) M-1. The anticancer and antibacterial properties of compounds were confirmed with the molecular docking simulation for their pharmacokinetic. As a result, the preliminary experimental data and a multi-criteria decision-making methodology (MCDM) indicated that the mono substituted indeno[1,2-b]quinoline amine derivatives, especially 3 a and 5, exhibit effective pharmacological properties. parameters and their interaction with related cells at the molecular level.Öğe In–Vitro Anticancer and Antibacterial Activities of Brominated Indeno[1,2-b]qinoline Amines Supported with Molecular Docking and MCDM**(John Wiley and Sons Inc, 2021) Aydın, Ali; Ökten, Salih; Erkan, Sultan; Bulut, Merve; Özcan, Evrencan; Tutar, Ahmet; Eren, TamerThe present study describes mono substituted indeno[1,2-b]quinolines (3 a–c and 5) have much more antiproliferative potentials than positive controls against A549, HeLa, MCF7 and Hep3B cell lines (IC50 values 1.1–29.6 ?g/mL) and show similar cytotoxicity (14.3 % to 19.8 %) to cells such as controls. Moreover, the mono substituted indeno[1,2-b]quinoline amines (3 a–c and 5) exhibit significant antimicrobial activity with MIC values between 15.62 ?g/mL and 250 ?g/mL. The compounds can also bind to DNA in the groove binding mode with a binding constant range of 1.1×103–1.1×105 M?1. The anticancer and antibacterial properties of compounds were confirmed with the molecular docking simulation for their pharmacokinetic. As a result, the preliminary experimental data and a multi-criteria decision-making methodology (MCDM) indicated that the mono substituted indeno[1,2-b]quinoline amine derivatives, especially 3 a and 5, exhibit effective pharmacological properties. parameters and their interaction with related cells at the molecular level. © 2021 Wiley-VCH GmbHÖğe Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities(Wiley, 2024) Misir, Busra A.; Derin, Yavuz; Okten, Salih; Aydin, Ali; Kocyigit, Umit M.; Sahin, Hatice; Tutar, AhmetIn this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies. The novel aryl substituted tacrine were efficiently synthesized and their anticancer potentials were highlighted in this study. Their inducing apoptosis, cell migration, and mitochondrial membrane potentials were screened. imageÖğe SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors(Assoc Pharmaceutical Teachers India, 2019) Okten, Salih; Ekiz, Makbule; Tutar, Ahmet; Butun, Burcu; Kocyigit, Umit Muhammet; Topcu, Gulacti; Gulcin, IlhamiBackground: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and H) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and H by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K-i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K-i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors.Öğe Synthesis and spectral properties of symmetrically arylated BODIPY dyes: Experimental and computational approach(Elsevier, 2023) Yilmaz, Rasit Fikret; Derin, Yavuz; Misir, Busra Albayrak; Atalay, Vildan Enisoglu; Tutar, Omer Faruk; Okten, Salih; Tutar, AhmetIn this study, a series of symmetrically arylated BODIPY dyes were synthesized using a pre-functionalization method, and their structures were characterized by several spectroscopic methods. The relationship between the aryl substitution pattern and the photophysical and electrochemical properties of the dyes was investigated using experimental and computational methods. It was found that electron-donating & pi;-conjugated groups at the meso position and electron-accepting & pi;-conjugated groups at the C3/C5 position led to blue-shifted spectra, while the opposite substitution pattern resulted in red-shifted spectra. Additionally, inductive electron-donating alkyl groups at the meso position produced a blue spectral shift and an alkyl group at the meso position significantly increased the fluorescence quantum yield compared to the arylated counterparts. Computational investigations revealed that a thioanisyl group at the C3/C5 position resulted in a significantly narrow band gap. These results provide valuable insights into the design and development of new BODIPY dyes with tailored properties for various applications.Öğe Synthesis, characterization, and SAR of arylated indenoquinoline-based cholinesterase and carbonic anhydrase inhibitors(Wiley-V C H Verlag Gmbh, 2018) Ekiz, Makbule; Tutar, Ahmet; Okten, Salih; Butun, Burcu; Kocyigit, Umit M.; Taslimi, Parham; Topcu, GuelactiWe report the synthesis of bromoindenoquinolines (15a-f) by Friedlander reactions in low yields (13-50%) and the conversion of the corresponding phenyl-substituted indenoquinoline derivatives 16-21 in high yields (80-96%) by Suzuki coupling reactions. To explore the structure-activity relationship (SAR), their inhibition potentials to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase cyctosolic (hCA I and II) enzymes were determined. Monophenyl (16-18) indenoquinolines significantly inhibited the AChE and BChE enzymes in ranges of IC50 37-57nM and 84-93nM, respectively, compared with their starting materials 15a-c and reference compounds (galanthamine and tacrine). On the other hand, these novel arylated indenoquinoline-based derivatives were effective inhibitors of the BChE, hCA I and II, BChE and AChE enzymes with K-i values in the range of 37 +/- 2.04 to 88640 +/- 1990nM for AChE, 120.94 +/- 37.06 to 1150.95 +/- 304.48nM for hCA I, 267.58 +/- 98.05 to 1568.16 +/- 438.67nM for hCA II, and 84 +/- 3.86 to 144120 +/- 2910nM for BChE. As a result, monophenyl indenoquinolines 16-18 may have promising anti-Alzheimer drug potential and 3,8-dibromoindenoquinoline amine (15f) can be novel hCA I and hCA II enzyme inhibitors.Öğe Synthesis, characterization, crystal structures, theoretical calculations and biological evaluations of novel substituted tacrine derivatives as cholinesterase and carbonic anhydrase enzymes inhibitors(Elsevier Science Bv, 2019) Okten, Salih; Ekiz, Makbule; Kocyigit, Umit Muhammet; Tutar, Ahmet; Celik, Ismail; Akkurt, Mehmet; Gulcin, IlhamiThe six and seven hydrocycle membered disilylanilino acridine (tacrine) analogues (9-11) were synthesized by one-pot procedures. The structures of novel silyl tacrine derivatives were characterized by NMR spectroscopy, elemental analysis and XRD investigations. The silyl substituted novel tacrine derivatives (9-11) were investigated as cholinesterase inhibitors and defined the relative role of AChE (Acetylcholinesterase) versus BChE (Butyrylcholinesterase) inhibition. Novel substituted tacrine derivatives are known as important inhibitors of Carbonic anhydrase (CA) isoenzymes I, and II (hCA I and II), therefore, the synthesized compounds (9-11) were investigated for inhibitory effects on the both CA isoenzymes. Additionally, we evaluated four different enzymes, which were inhibited in the very low nanomolar (nM) range by these compounds. According to the present studies, for AChE, BChE, hCA I and II, the ranges of results are recorded as 30.26 +/- 6.71-117.54 +/- 42.22 nM, 22.45 +/- 5.81-77.41 +/- 4.02 nM, 57.28 +/- 22.16-213.41 +/- 82.75 nM and 46.95 +/- 11.32-274.94 +/- 62.15 nM, respectively. (C) 2018 Elsevier B.V. All rights reserved.Öğe The Anticancer Potentials of Substituted Indeno[1,2-b]quinoline Amines against HT29 and SW620: Experimental and In silico Approach(Bentham Science Publishers, 2024) Ökten, Salih; Aydın, Ali; Erkan, Sultan; Tutar, AhmetBackground: This study aimed the determination of the antiproliferative and cytotoxic activities of recently prepared indeno [1,2-b]quinoline amines against colon carcinoma, HT29 and SW620 cell lines by using cell proliferation and cytotoxicity assays. Methods: In vitro inhibition of cell proliferation of indenoquinoline derivatives was determined with an MTT cell proliferation assay. On the other hand, their cell cytotoxicities and apoptotic potential were investigated by LDH cytotoxicity and DNA laddering assays. Moreover, molecular docking studies were performed between the compounds and PDB ID: 1OLG and 4LVT target proteins using virtual scanning techniques. Results: Most of the compounds (1, 3, and 7-9) exhibit much more potent antiproliferative activity than positive controls against HT29 and SW620 cell lines (IC50 values 1.1-4.1 µg/mL) and show slightly toxic properties (percent cytotoxicity 9.8% to 33.5%) to cells compared to positive control. On the other hand, it was determined that effective compounds 1, 2, 3 and 9 stimulated apoptosis on HT29 and SW620. Moreover, the anticancer effect of the recent indeno[1,2-b]quinoline amine derivatives was investigated with the help of molecular docking simulations for their pharmacokinetics. The molecular docking results displayed that mono bromo (1-3) and phenyl (7-9) substituted indeno [1,2-b]quinoline amines interact with mutated p53 and protein Blc-2 residues with hydrogen bonding and polar interactions, respectively. Conclusion: As a result, the preliminary experimental data and in silico studies indicated that the monosubstituted indenoquinoline amine derivatives, especially 1, 3, and 7-9, exhibit effective pharmacological properties. © 2024 Bentham Science Publishers.Öğe Türk vergi hukukunda sahte veya muhteviyatı itibariyle yanıltıcı belge düzenleme ve kullanma(Kırıkkale Üniversitesi, 2022) Tutar, Ahmet; Ömercioğlu, Üyesi AbdullahSahte veya muhteviyatı itibariyle yanıltıcı belge düzenleme ve kullanma fiilleri, Türk vergi hukukunun en temel sorunlarından biri haline gelmiştir. Bu fiillerden kaynaklanan suçlar ülkemizde yaygın olarak işlenmektedir. Sahte veya muhteviyatı itibariyle yanıltıcı belge düzenlenmesinin veya kullanılmasının amacı, ödenmesi gereken verginin hiç ödenmemesi ya da olduğundan az ödenmesidir. Bu fiillerin gerekli tespitler yapılarak asgari seviyeye indirilmesi, vergi gelirlerinin artması ve kamu düzeninin tesisi bakımından oldukça önemlidir. Çalışmamızın birinci bölümünde, sahte belge veya muhteviyatı itibariyle yanıltıcı belge kavramları üzerinde durularak, sahte veya muhteviyatı itibariyle yanıltıcı belge düzenleme ya da kullanma nedenlerine, düzenleyenler hakkında yapılan genel tespitler ile bir belgenin sahteliğini ispat etme araçlarına ve bu suçların önlenmesi için yapılması gerekenlere yer verilmiştir. İkinci bölümde ise, sahte veya muhteviyatı itibariyle yanıltıcı belge düzenlemenin ya da kullanmanın vergi hukuku açısından ve vergi ceza hukuku açısından doğurduğu sonuçlara değinilerek, söz konusu fiillerden kaynaklanan suç ve kabahatlerin "ne bis in idem" ilkesi ile uyum sorunu detaylı olarak irdelenmiştir.
