Ismail Yalcin - Academia.edu (original) (raw)
Papers by Ismail Yalcin
Bu çalışmada, rayserin yatay hareketi incelenmektedir. Rayser, platform veya teknede bulunan gerd... more Bu çalışmada, rayserin yatay hareketi incelenmektedir. Rayser, platform veya teknede bulunan gerdirici aygıtı ile gerilmekte olan düşey asılı duran bir kiriştir. Bu kiriş; dalgalar, akıntı ve yüzen platform veya tekne hareketi ile zorlanmaktadır. Dördüncü mertebeden kısmi türevli hareket denklemi, Euler kiriş-kolon teorisi gözönüne alınarak, varyasyonel bir yöntem kullanılarak elde edilmiştir. Hidrodinamik kuvvetler, Morison Denklemi'nin düzeltilmiş bir şekli kullanılarak değerlendirilmektedir. Bu denklem ampirik olmasına rağmen, rayser gibi hidrodinamik geçirgen açık deniz yapılarının dizaynında yaygın bir şekilde kullanılmaktadır. Lineer dalga teorisi, su parçacığının kinematiğinde kullanılmaktadır. Daha sonra, uzun rayserin statik ve dinamik analizi yapılmaktadır. Her iki analizde de, yönetici hareket denklemi Bessel diferansiyel denklemine dönüştürülerek çözüm aranmaktadır. Statik analizde kritik efektif boyuna kuvvet ve bu kuvvetin yeri de hesaplanmaktadır. Derin su analizinde, hidrodinamik kuvvetler dalga boyunun yarısı kadar bir derinlikten itibaren kayboldukları için, dalganın direnç ve atalet kuvvetleri gözönüne alınmamış, onun yerine yüzeyde dalgadan kaynaklanan surge hareketinin genliği sınır şartı olarak kullanılmıştır. Hazırlanan bilgisayar programlarının doğruluğu, statik ve dinamik analizler için kullanılan örnek veriler işlenerek karşılaştırmalı olarak gösterilmektedir. Daha sonra, Amerikan Petrol Enstitüsü'nün bültenindeki 1500 ft (457.2 m) su derinlikli konvansiyonel rayser incelenmiştir. Statik analizde API 1500-0-1, dinamik analizde API 1500-20-1-D olarak adlandırılan bu rayserin verileri kullanılarak bulunan sonuçlar, enstitünün test için sunduğu, dokuz bağımsız araştırmacı tarafından elde edilmiş birleşik sonuçların ortalaması ile karşılaştırılmıştır. Bulunan sonuçların bu sonuçlar ile uyumlu oldukları görülmektedir.
DARU Journal of Pharmaceutical Sciences, 2019
Background The numbers of topoisomerase I targeted drugs on the market are very limited although ... more Background The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. Objectives In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. Methods We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. Results While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC 50 :8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC 50 :0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC 50 :0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R 2 position were play a role for increasing of its poisonous effect. Conclusion As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Keywords Benzoxazine. Anticancer. Topoisomerase I. Catalytic inhibitor. Topoisomerase I poison Key-Points • Benzoxazine derivatives inhibit human DNA topoisomerase I action. • BONC-001 inhibited catalytic activity of hTopo I by interacting with DNA binding site of the enzyme. • OH group at the 2nd position of benzoxazine ring was very important for catalytic inhibition. • BONC-013, 77 times more effective than CPT, inhibited hTopo I activity by stabilizing covalent enzyme-DNA complex. • The attachment of methyl group of the R1 position seemed to play a role for poison effect.
Journal of Electroanalytical Chemistry, 2016
In this study, we developed an electrochemical DNA biosensor based on a poly-3-amino-1,2,4-triazo... more In this study, we developed an electrochemical DNA biosensor based on a poly-3-amino-1,2,4-triazole-5-thiol (P(AT)) film modified glassy carbon electrode (GCE/P(AT)). For the first time, this electrode was used for the determination of a new benzimidazole molecule, 2-(2-phenyl ethyl)-5-methylbenzimidazole (BNN-17). The electrochemical behavior of the GCE/P(AT) electrode was investigated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Differential pulse voltammetry (DPV) was carried out to obtain the change in the oxidation signals of the guanine and adenine before and after interaction with the BNN-17. Under the optimum conditions, a linear dependence of the guanine oxidation signals was observed when the BNN-17 concentration was in the range of 0.213-32.03 μmol L −1 (R 2 = 0.991). The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.063 μmol L −1 and 0.21 μmol L −1 , respectively. The influence of potential interfering substances on BNN-17 determination was studied. Finally, the GCE/P(AT)/dsDNA electrode was utilized for the determination of BNN-17 in serum samples which gave sensitive, accurate, and precise results. The binding mode of BNN-17 with dsDNA was investigated using DPV, UV-vis absorption spectroscopy, and molecular docking methods. All of the experimental results indicated that BNN-17 preferred to bind on the minor groove of dsDNA. The results obtained from the experimental data were in good agreement with the molecular docking studies.
Revista Cubana de Química, 2005
Ankara Universitesi Eczacilik Fakultesi Dergisi, 1983
Current topics in medicinal chemistry, 2020
BACKGROUND Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatmen... more BACKGROUND Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death. METHODS Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs. RESULT Docking studies results were clarified bindin...
The resistance-nodulation-cell division family (RND) efflux pumps exemplify a unique phenomenon w... more The resistance-nodulation-cell division family (RND) efflux pumps exemplify a unique phenomenon with drug resistance in different gram negative bacterial strains as a single mechanism causing resistance against several different classes of antibiotics. In Escherichia coli AG102 and Acinetobacter baumannii SBMox2 strains the well characterized RND efflux pumps are AcrAB-TolC and the AdeABC respectively. Most of the antibiotics were found to be substrates for these pumps by increasing the expression of the efflux pump genes, leading to multidrug resistance (MDR) and the treatment failure and death caused by these gram negative bacterial infections or underlying diseases are common (Sun et al., 2014). Consequently, the need of searching new therapeutic solutions that suppress the activity of efflux pumps and restore the sensitivity of commonly used antibiotic is essential. RND efflux pumps, which are only found in Gram-negative bacteria, have a tripartite composition. RND type efflux p...
![Research paper thumbnail of FTIR, Raman and DFT studies on 2-[4-(4-ethylbenzamido)phenyl]benzothiazole and 2-[4-(4-nitrobenzamido)phenyl]benzothiazole supported by differential scanning calorimetry](https://attachments.academia-assets.com/96462822/thumbnails/1.jpg)
](Journal of Molecular Structure, 2020
FTIR, Raman and DFT studies on 2-[4-(4-ethylbenzamido)phenyl] benzothiazole and 2-[4-(4-nitrobenz... more FTIR, Raman and DFT studies on 2-[4-(4-ethylbenzamido)phenyl] benzothiazole and 2-[4-(4-nitrobenzamido)phenyl]benzothiazole supported by differential scanning calorimetry
SAR and QSAR in Environmental Research, 2017
Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of hum... more Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of human tumours and is involved in the development of resistance to several anticancer drugs. So, it has become an important target in cancer treatment. In this study, 12 benzothiazole derivatives were synthesized and screened for their in vitro inhibitory activity for hGSTP1-1. Among these compounds, two of them (compounds #2 and #5) have been found to be the leads when compared with the reference drug etoposide. In order to analyse the structure-activity relationships (SARs) and to investigate the binding side interactions of the observed lead compounds, a HipHop pharmacophore model was generated and the molecular docking studies were performed by using CDocker method. In conclusion, it is observed that the lead compounds #2 and #5 possessed inhibitory activity on the hGSTP1-1 by binding to the H-site as a substrate in which the para position of the phenyl ring of the benzamide moiety on the benzothiazole ring is important. Substitution at this position with a hydrophobic group that reduces the electron density at the phenyl ring is required for the interaction with the H side active residue Tyr108.
Croatica Chemica Acta, 2013
A new series of 2-[4-(4-substitutedbenzamido / phenylacetamido / phenylpropionamido) benzyl / phe... more A new series of 2-[4-(4-substitutedbenzamido / phenylacetamido / phenylpropionamido) benzyl / phenyl]benzothiazole derivatives (6a−6w) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli with their drug-resistant isolates and a yeast Candida albicans. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 200 and 6.25 µg/ml. Compounds 6e and 6j exhibited the greatest activity with MIC values of 6.25 µg/ml against Pseudomonas aeruginosa, and Staphylococcus aureus isolate, respectively.
Journal of Pharmacy and Pharmacology, 2017
Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer ... more Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
Heterocyclic compounds, structurally similar to natural biochemical molecules, are usually used f... more Heterocyclic compounds, structurally similar to natural biochemical molecules, are usually used for the anticancer drug design. Since they can interact with DNA, they are able to show mutagenic or genotoxic effects. They show their anticancer effects by inhibiting cell proliferation and inducing apoptosis. The first step to select effective compounds is using simple, rapid and inexpensive in vitro tests. Although there are several mutagenicity and genotoxicity tests for this purpose, Ames test is the main mutagenicity test that can be carried out in many laboratories.
Design of new anticancer prodrugs is important source to the development of antitumoral agents th... more Design of new anticancer prodrugs is important source to the development of antitumoral agents that can be effective on resistant cancer cell types and have fewer side effects. The first step is to select effective compounds by simple, rapid and inexpensive in vitro tests. Although, there are several mutagenicity and genotoxicity tests for this purpose, Ames test is the main mutagenicity test that can be carried out in many laboratories. In our study, we have studied 5 new benzothiazole derivatives, which are bicylic heterocyclic compounds. These compounds were taken advantages of some mainful characteristics like showing mutagenic effects, causing aneuploidy in chromosomes, inducing apoptosis and inhibiting cell proliferation. Thanks to their such kinds of features, benzothiazole derivates are used in the synthesis of anticancer drugs. To evaluate mutagenic potentials of compounds Ames mutagenicity test, and plate incorporation assay, have been used based on the method of Maron and Ames. We used salmonella typhimirium TA98 and TA100 strain in the test system. Also metabolic activation system (S9 fractions) was added for the evaluation of mutagenic potential of metabolites of the compounds. All determinations were made in triplicate. Results were evaluated with Student’s-T test with the confidence interval 95-99%. According to the assay results, in the absence of the metabolic activation system 5 (50 and 75 μg/plate), 6 (50-150 μg/plate) numbered compounds showed mutagenic effects on S. typhimurium TA98 while they have no mutagenic potentials in S. typhimurium TA100 strain. None of the tested compounds showed mutagenic effect in the presence of the metabolic activation system.
Sonuc urunler o-aminotiyofenolden hareketle hazirlanmistir. Oncelikle, o-aminotiyofenol, p-aminob... more Sonuc urunler o-aminotiyofenolden hareketle hazirlanmistir. Oncelikle, o-aminotiyofenol, p-aminobenzoik asid veya p-aminofenilasetik asit ile PPA icinde isitilarak 2-(4-aminofenil/benzil)benzotiyazol hazirlanmis; takiben, para konumundaki amino grubu cesitli acil klorurleri ile muamele edilerek 2-[4-(4-substitue-benzamido / fenilasetamido / 3-fenilpropanamido)fenil / benzil] benzotiyazol turevlerinin sentezi gerceklestirilmistir.Sentezlenen bilesiklerin safliklari Ince Tabaka Kromatografisi ile kontrol edildikten sonra, erime dereceleri saptanmistir. Bilesiklerin yapilari IR, 1H-NMR, Kutle ve Elementel Analiz Yontemleri kullanilarak aydinlatilmis ve elde edilen veriler bulgular kisminda verilmistir.Sentezlenen bilesiklerin in vitro mikrobiyolojik aktiviteleri incelenmek uzere antibakteriyel aktivite icin, Gram-negatif bakterilerden; Klebsiella pneumoniae izolati [Genislemis Spektrumlu Beta Laktamaz enzimi (GSBL) icerir], Pseudomonas aeruginosa izolati (gentamisine direncli), Escheri...
Asian Journal of Chemical Sciences, 2018
QSAR analysis of thiosemicarbazone derivatives exposing RNR inhibitory activities [1] was perform... more QSAR analysis of thiosemicarbazone derivatives exposing RNR inhibitory activities [1] was performed for 21 compounds. Among these compounds, 13 of them were reported with inhibitory concentration (IC 50) in the l M range. The inhibitory concentration of those compounds was converted into-logIC 50 before being correlated with the structural features. The quantum chemical calculations have been carried out at the B3LYP at Complete Basis set (CBS) level of theory using Gaussian-09 series of program package. The density functional theory (DFT), Becke's three parameter exchange function along with the Lee-Yang-Parr correlation function (B3LYP) were considered to calculate the quantum chemical descriptors such as HOMO, LUMO, Energy gap, Hardness, Softness, Chemical potential and Dipole moment of the investigated molecules. The variables make a unique statistically significant contribution (p < 0.05). According to their beta values, electronegativity showed the biggest beta coefficient (-13.225). It has been revealed that variable has a unique contribution to a stronger explanation of dependent variables. Beta values for the electrofugality was slightly lower (8.350) , showing least contribution for rest of the elements. Other variables (Energy gap, chemical potential, nucleofugality) measured for this model was statistically significant.
SAR and QSAR in Environmental Research, 2015
The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resi... more The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.
In vivo (Athens, Greece)
Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for in... more Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for induction and inhibition of apoptosis on tumor cells (L5718, mouse lymphoma cell line containing the human mdr-1 gene). For evaluation of apoptosis, the cells were stained with FITC-labelled Annexin-V and propidium iodide and the results were analysed by flow cytometry. Nine of these substances were also checked for reversal of multidrug resistance. The reversal of multidrug resistance was determined by measuring the rhodamine-123 accumulation in the cancer cells. Rhodamine-123 shows a green fluorescence and its intracellular concentration correlates well with the inhibition of efflux pump activity. Three of the tested compounds, 5-(p-nitrobenzamido)-2-benzylbenzoxazole (BD-3), 6-methyl-2-(o-chlorophenyl) benzoxazole (A-9) and 5-(p-nitrophenoxyacetamido)-2-phenylbenzoxazole (D-30), showed an increased apoptotic effect on mouse lymphoma cells. Moreover, compounds BD-3, A-9 and 5-(2-thienylc...
SAR and QSAR in Environmental Research, 2014
There has been considerable interest in DNA topoisomerases over the last decade, as they have bee... more There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.
SAR and QSAR in Environmental Research, 2008
Bu çalışmada, rayserin yatay hareketi incelenmektedir. Rayser, platform veya teknede bulunan gerd... more Bu çalışmada, rayserin yatay hareketi incelenmektedir. Rayser, platform veya teknede bulunan gerdirici aygıtı ile gerilmekte olan düşey asılı duran bir kiriştir. Bu kiriş; dalgalar, akıntı ve yüzen platform veya tekne hareketi ile zorlanmaktadır. Dördüncü mertebeden kısmi türevli hareket denklemi, Euler kiriş-kolon teorisi gözönüne alınarak, varyasyonel bir yöntem kullanılarak elde edilmiştir. Hidrodinamik kuvvetler, Morison Denklemi'nin düzeltilmiş bir şekli kullanılarak değerlendirilmektedir. Bu denklem ampirik olmasına rağmen, rayser gibi hidrodinamik geçirgen açık deniz yapılarının dizaynında yaygın bir şekilde kullanılmaktadır. Lineer dalga teorisi, su parçacığının kinematiğinde kullanılmaktadır. Daha sonra, uzun rayserin statik ve dinamik analizi yapılmaktadır. Her iki analizde de, yönetici hareket denklemi Bessel diferansiyel denklemine dönüştürülerek çözüm aranmaktadır. Statik analizde kritik efektif boyuna kuvvet ve bu kuvvetin yeri de hesaplanmaktadır. Derin su analizinde, hidrodinamik kuvvetler dalga boyunun yarısı kadar bir derinlikten itibaren kayboldukları için, dalganın direnç ve atalet kuvvetleri gözönüne alınmamış, onun yerine yüzeyde dalgadan kaynaklanan surge hareketinin genliği sınır şartı olarak kullanılmıştır. Hazırlanan bilgisayar programlarının doğruluğu, statik ve dinamik analizler için kullanılan örnek veriler işlenerek karşılaştırmalı olarak gösterilmektedir. Daha sonra, Amerikan Petrol Enstitüsü'nün bültenindeki 1500 ft (457.2 m) su derinlikli konvansiyonel rayser incelenmiştir. Statik analizde API 1500-0-1, dinamik analizde API 1500-20-1-D olarak adlandırılan bu rayserin verileri kullanılarak bulunan sonuçlar, enstitünün test için sunduğu, dokuz bağımsız araştırmacı tarafından elde edilmiş birleşik sonuçların ortalaması ile karşılaştırılmıştır. Bulunan sonuçların bu sonuçlar ile uyumlu oldukları görülmektedir.
DARU Journal of Pharmaceutical Sciences, 2019
Background The numbers of topoisomerase I targeted drugs on the market are very limited although ... more Background The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. Objectives In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. Methods We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. Results While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC 50 :8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC 50 :0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC 50 :0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R 2 position were play a role for increasing of its poisonous effect. Conclusion As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Keywords Benzoxazine. Anticancer. Topoisomerase I. Catalytic inhibitor. Topoisomerase I poison Key-Points • Benzoxazine derivatives inhibit human DNA topoisomerase I action. • BONC-001 inhibited catalytic activity of hTopo I by interacting with DNA binding site of the enzyme. • OH group at the 2nd position of benzoxazine ring was very important for catalytic inhibition. • BONC-013, 77 times more effective than CPT, inhibited hTopo I activity by stabilizing covalent enzyme-DNA complex. • The attachment of methyl group of the R1 position seemed to play a role for poison effect.
Journal of Electroanalytical Chemistry, 2016
In this study, we developed an electrochemical DNA biosensor based on a poly-3-amino-1,2,4-triazo... more In this study, we developed an electrochemical DNA biosensor based on a poly-3-amino-1,2,4-triazole-5-thiol (P(AT)) film modified glassy carbon electrode (GCE/P(AT)). For the first time, this electrode was used for the determination of a new benzimidazole molecule, 2-(2-phenyl ethyl)-5-methylbenzimidazole (BNN-17). The electrochemical behavior of the GCE/P(AT) electrode was investigated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Differential pulse voltammetry (DPV) was carried out to obtain the change in the oxidation signals of the guanine and adenine before and after interaction with the BNN-17. Under the optimum conditions, a linear dependence of the guanine oxidation signals was observed when the BNN-17 concentration was in the range of 0.213-32.03 μmol L −1 (R 2 = 0.991). The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.063 μmol L −1 and 0.21 μmol L −1 , respectively. The influence of potential interfering substances on BNN-17 determination was studied. Finally, the GCE/P(AT)/dsDNA electrode was utilized for the determination of BNN-17 in serum samples which gave sensitive, accurate, and precise results. The binding mode of BNN-17 with dsDNA was investigated using DPV, UV-vis absorption spectroscopy, and molecular docking methods. All of the experimental results indicated that BNN-17 preferred to bind on the minor groove of dsDNA. The results obtained from the experimental data were in good agreement with the molecular docking studies.
Revista Cubana de Química, 2005
Ankara Universitesi Eczacilik Fakultesi Dergisi, 1983
Current topics in medicinal chemistry, 2020
BACKGROUND Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatmen... more BACKGROUND Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death. METHODS Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs. RESULT Docking studies results were clarified bindin...
The resistance-nodulation-cell division family (RND) efflux pumps exemplify a unique phenomenon w... more The resistance-nodulation-cell division family (RND) efflux pumps exemplify a unique phenomenon with drug resistance in different gram negative bacterial strains as a single mechanism causing resistance against several different classes of antibiotics. In Escherichia coli AG102 and Acinetobacter baumannii SBMox2 strains the well characterized RND efflux pumps are AcrAB-TolC and the AdeABC respectively. Most of the antibiotics were found to be substrates for these pumps by increasing the expression of the efflux pump genes, leading to multidrug resistance (MDR) and the treatment failure and death caused by these gram negative bacterial infections or underlying diseases are common (Sun et al., 2014). Consequently, the need of searching new therapeutic solutions that suppress the activity of efflux pumps and restore the sensitivity of commonly used antibiotic is essential. RND efflux pumps, which are only found in Gram-negative bacteria, have a tripartite composition. RND type efflux p...
Journal of Molecular Structure, 2020
FTIR, Raman and DFT studies on 2-[4-(4-ethylbenzamido)phenyl] benzothiazole and 2-[4-(4-nitrobenz... more FTIR, Raman and DFT studies on 2-[4-(4-ethylbenzamido)phenyl] benzothiazole and 2-[4-(4-nitrobenzamido)phenyl]benzothiazole supported by differential scanning calorimetry
SAR and QSAR in Environmental Research, 2017
Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of hum... more Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of human tumours and is involved in the development of resistance to several anticancer drugs. So, it has become an important target in cancer treatment. In this study, 12 benzothiazole derivatives were synthesized and screened for their in vitro inhibitory activity for hGSTP1-1. Among these compounds, two of them (compounds #2 and #5) have been found to be the leads when compared with the reference drug etoposide. In order to analyse the structure-activity relationships (SARs) and to investigate the binding side interactions of the observed lead compounds, a HipHop pharmacophore model was generated and the molecular docking studies were performed by using CDocker method. In conclusion, it is observed that the lead compounds #2 and #5 possessed inhibitory activity on the hGSTP1-1 by binding to the H-site as a substrate in which the para position of the phenyl ring of the benzamide moiety on the benzothiazole ring is important. Substitution at this position with a hydrophobic group that reduces the electron density at the phenyl ring is required for the interaction with the H side active residue Tyr108.
Croatica Chemica Acta, 2013
A new series of 2-[4-(4-substitutedbenzamido / phenylacetamido / phenylpropionamido) benzyl / phe... more A new series of 2-[4-(4-substitutedbenzamido / phenylacetamido / phenylpropionamido) benzyl / phenyl]benzothiazole derivatives (6a−6w) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli with their drug-resistant isolates and a yeast Candida albicans. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 200 and 6.25 µg/ml. Compounds 6e and 6j exhibited the greatest activity with MIC values of 6.25 µg/ml against Pseudomonas aeruginosa, and Staphylococcus aureus isolate, respectively.
Journal of Pharmacy and Pharmacology, 2017
Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer ... more Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
Heterocyclic compounds, structurally similar to natural biochemical molecules, are usually used f... more Heterocyclic compounds, structurally similar to natural biochemical molecules, are usually used for the anticancer drug design. Since they can interact with DNA, they are able to show mutagenic or genotoxic effects. They show their anticancer effects by inhibiting cell proliferation and inducing apoptosis. The first step to select effective compounds is using simple, rapid and inexpensive in vitro tests. Although there are several mutagenicity and genotoxicity tests for this purpose, Ames test is the main mutagenicity test that can be carried out in many laboratories.
Design of new anticancer prodrugs is important source to the development of antitumoral agents th... more Design of new anticancer prodrugs is important source to the development of antitumoral agents that can be effective on resistant cancer cell types and have fewer side effects. The first step is to select effective compounds by simple, rapid and inexpensive in vitro tests. Although, there are several mutagenicity and genotoxicity tests for this purpose, Ames test is the main mutagenicity test that can be carried out in many laboratories. In our study, we have studied 5 new benzothiazole derivatives, which are bicylic heterocyclic compounds. These compounds were taken advantages of some mainful characteristics like showing mutagenic effects, causing aneuploidy in chromosomes, inducing apoptosis and inhibiting cell proliferation. Thanks to their such kinds of features, benzothiazole derivates are used in the synthesis of anticancer drugs. To evaluate mutagenic potentials of compounds Ames mutagenicity test, and plate incorporation assay, have been used based on the method of Maron and Ames. We used salmonella typhimirium TA98 and TA100 strain in the test system. Also metabolic activation system (S9 fractions) was added for the evaluation of mutagenic potential of metabolites of the compounds. All determinations were made in triplicate. Results were evaluated with Student’s-T test with the confidence interval 95-99%. According to the assay results, in the absence of the metabolic activation system 5 (50 and 75 μg/plate), 6 (50-150 μg/plate) numbered compounds showed mutagenic effects on S. typhimurium TA98 while they have no mutagenic potentials in S. typhimurium TA100 strain. None of the tested compounds showed mutagenic effect in the presence of the metabolic activation system.
Sonuc urunler o-aminotiyofenolden hareketle hazirlanmistir. Oncelikle, o-aminotiyofenol, p-aminob... more Sonuc urunler o-aminotiyofenolden hareketle hazirlanmistir. Oncelikle, o-aminotiyofenol, p-aminobenzoik asid veya p-aminofenilasetik asit ile PPA icinde isitilarak 2-(4-aminofenil/benzil)benzotiyazol hazirlanmis; takiben, para konumundaki amino grubu cesitli acil klorurleri ile muamele edilerek 2-[4-(4-substitue-benzamido / fenilasetamido / 3-fenilpropanamido)fenil / benzil] benzotiyazol turevlerinin sentezi gerceklestirilmistir.Sentezlenen bilesiklerin safliklari Ince Tabaka Kromatografisi ile kontrol edildikten sonra, erime dereceleri saptanmistir. Bilesiklerin yapilari IR, 1H-NMR, Kutle ve Elementel Analiz Yontemleri kullanilarak aydinlatilmis ve elde edilen veriler bulgular kisminda verilmistir.Sentezlenen bilesiklerin in vitro mikrobiyolojik aktiviteleri incelenmek uzere antibakteriyel aktivite icin, Gram-negatif bakterilerden; Klebsiella pneumoniae izolati [Genislemis Spektrumlu Beta Laktamaz enzimi (GSBL) icerir], Pseudomonas aeruginosa izolati (gentamisine direncli), Escheri...
Asian Journal of Chemical Sciences, 2018
QSAR analysis of thiosemicarbazone derivatives exposing RNR inhibitory activities [1] was perform... more QSAR analysis of thiosemicarbazone derivatives exposing RNR inhibitory activities [1] was performed for 21 compounds. Among these compounds, 13 of them were reported with inhibitory concentration (IC 50) in the l M range. The inhibitory concentration of those compounds was converted into-logIC 50 before being correlated with the structural features. The quantum chemical calculations have been carried out at the B3LYP at Complete Basis set (CBS) level of theory using Gaussian-09 series of program package. The density functional theory (DFT), Becke's three parameter exchange function along with the Lee-Yang-Parr correlation function (B3LYP) were considered to calculate the quantum chemical descriptors such as HOMO, LUMO, Energy gap, Hardness, Softness, Chemical potential and Dipole moment of the investigated molecules. The variables make a unique statistically significant contribution (p < 0.05). According to their beta values, electronegativity showed the biggest beta coefficient (-13.225). It has been revealed that variable has a unique contribution to a stronger explanation of dependent variables. Beta values for the electrofugality was slightly lower (8.350) , showing least contribution for rest of the elements. Other variables (Energy gap, chemical potential, nucleofugality) measured for this model was statistically significant.
SAR and QSAR in Environmental Research, 2015
The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resi... more The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.
In vivo (Athens, Greece)
Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for in... more Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for induction and inhibition of apoptosis on tumor cells (L5718, mouse lymphoma cell line containing the human mdr-1 gene). For evaluation of apoptosis, the cells were stained with FITC-labelled Annexin-V and propidium iodide and the results were analysed by flow cytometry. Nine of these substances were also checked for reversal of multidrug resistance. The reversal of multidrug resistance was determined by measuring the rhodamine-123 accumulation in the cancer cells. Rhodamine-123 shows a green fluorescence and its intracellular concentration correlates well with the inhibition of efflux pump activity. Three of the tested compounds, 5-(p-nitrobenzamido)-2-benzylbenzoxazole (BD-3), 6-methyl-2-(o-chlorophenyl) benzoxazole (A-9) and 5-(p-nitrophenoxyacetamido)-2-phenylbenzoxazole (D-30), showed an increased apoptotic effect on mouse lymphoma cells. Moreover, compounds BD-3, A-9 and 5-(2-thienylc...
SAR and QSAR in Environmental Research, 2014
There has been considerable interest in DNA topoisomerases over the last decade, as they have bee... more There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.
SAR and QSAR in Environmental Research, 2008