Browsing by Author "Uçar, Gülberk"

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Citation Count: 1
2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması
(2018) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Amaç: Nöromediatörlerin yıkımından sorumlu olanmonoamin oksidaz (MAO) enziminin izoformlarının(MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu;MAO inhibitörlerinin depresyon, Parkinson ve Alzheimerhastalığı gibi hastalıkların tedavisinde kullanıldığıbilinmektedir. Grubumuzca daha etkin, tersinir ve az yanetkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmişve bu bileşiğin insan MAO enzimini (hMAO) inhibe etmeyeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ileetkileşimi, moleküler modelleme çalışmaları ile detaylıbir şekilde araştırılmıştır. Sentezlenen yeni bileşiğinhMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarakinhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinsonve Alzheimer hastalıklarının tedavisinde ümit verici birilaç etken maddesi olabileceği düşünülmektedir.Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenonile p-tolualdehit’in metanol içinde KOH varlığındareaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)-3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4-metil şalkon) bileşiği sentez edilmiştir. Daha sonraelde edilen bu bileşiğin etanol içerisinde geri çevirensoğutucu altında izonikotinik asit hidrazit ile muameleedilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5-dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentezedilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ileetkileşimi, ticari tayin kiti kullanılarak fluorometrik biryöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşikile hMAO arasındaki etkileşimler, moleküler modellemeçalışmaları ile aydınlatılmıştır.Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass,1H-NMR ve elemental analiz yöntemleri kullanılarakdoğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin,seçici, tersinir, toksik olmayan bir hMAO-B inhibitörüolduğu ve inhibisyonun yarışmalı olduğu görülmüştür.Moleküler yerleştirme programı kullanılarak bileşiğinhMAO-B enziminin aktif bölgesinde hangi amino asit yanzincirleri ile ne tür girişimleri yaptığı belirlenmiştir.Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-Benzimini kuvvetle, seçici, yarışmalı ve tersinir olarakinhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçiciama tersinmez MAO-B inhibitörü olan selejilin’den dahaetkin ve seçici, tersinir olarak hMAO-B enzimini inhibeetmiştir ve Parkinson ile Alzheimer hastalığı tedavisindekullanılabilecek bir ilaç etken maddesi olarak ümitvadetmektedir.
Citation Count: 0
"2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması"
(Türkiye Halk Sağlığı Kurumu, 2018) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Amaç: Nöromediatörlerin yıkımından sorumlu olan monoamin oksidaz (MAO) enziminin izoformlarının (MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu; MAO inhibitörlerinin depresyon, Parkinson ve Alzheimer hastalığı gibi hastalıkların tedavisinde kullanıldığı bilinmektedir. Grubumuzca daha etkin, tersinir ve az yan etkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmiş ve bu bileşiğin insan MAO enzimini (hMAO) inhibe etme yeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ile etkileşimi, moleküler modelleme çalışmaları ile detaylı bir şekilde araştırılmıştır. Sentezlenen yeni bileşiğin hMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarak inhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinson ve Alzheimer hastalıklarının tedavisinde ümit verici bir ilaç etken maddesi olabileceği düşünülmektedir. Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenon ile p-tolualdehit’in metanol içinde KOH varlığında reaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)- 3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4- metil şalkon) bileşiği sentez edilmiştir. Daha sonra elde edilen bu bileşiğin etanol içerisinde geri çeviren soğutucu altında izonikotinik asit hidrazit ile muamele edilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5- dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentez edilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ile etkileşimi, ticari tayin kiti kullanılarak fluorometrik bir yöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşik ile hMAO arasındaki etkileşimler, moleküler modelleme çalışmaları ile aydınlatılmıştır. Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass, 1H-NMR ve elemental analiz yöntemleri kullanılarak doğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin, seçici, tersinir, toksik olmayan bir hMAO-B inhibitörü olduğu ve inhibisyonun yarışmalı olduğu görülmüştür. Moleküler yerleştirme programı kullanılarak bileşiğin hMAO-B enziminin aktif bölgesinde hangi amino asit yan zincirleri ile ne tür girişimleri yaptığı belirlenmiştir. Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-B enzimini kuvvetle, seçici, yarışmalı ve tersinir olarak inhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçici ama tersinmez MAO-B inhibitörü olan selejilin’den daha etkin ve seçici, tersinir olarak hMAO-B enzimini inhibe etmiştir ve Parkinson ile Alzheimer hastalığı tedavisinde kullanılabilecek bir ilaç etken maddesi olarak ümit vadetmektedir.
Citation Count: 18
Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity
(Wiley, 2019) Yelekçi, Kemal; Sarıgül, Sevgi; Bultinck, Patrick; Herrebout, Wouter; Doğan, İlknur; Yelekçi, Kemal; Uçar, Gülberk; Kelekçi, Nesrin Gökhan
A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (K-i = 0.85 x 10(-3) +/- 0.05 x 10(-3) mu M and SI: 2.35 x 10(-5)) whereas S was determined as poorer compound than R in terms of K-i and SI (0.184 +/- 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.
Citation Count: 0
Design and synthesis of novel 2-pyrazoline analogues and their hMAO inhibitory activities
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Evranos-Aksoz, Begum; Yabanoglu-Çiftçi, Samiye; Yelekçi, Kemal
[Abstract Not Available]
Citation Count: 5
Design, Synthesis and hMAO Inhibitory Screening of Novel 2-Pyrazoline Analogues
(Bentham Science Publ Ltd, 2017) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Aim and Objective: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. Materials and Methods: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. Results: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004 +/- 0.001 and 0.005 +/- 0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10(-5) and 0.003, respectively). Both of these compounds were found non toxic at 1 mu M, 5 mu M and 25 mu M concentrations. Conclusion: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)- 4,5-dihydropyrazol-1-yl)(phenyl) methanone and (3-(2-hydroxy-4-methoxy phenyl)5- p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
Citation Count: 26
Flavonoids from Sideritis Species: Human Monoamine Oxidase (hMAO) Inhibitory Activities Molecular Docking Studies and Crystal Structure of Xanthomicrol
(MDPI, 2015) Yelekçi, Kemal; Baysal, Ipek; Çiftçi-Yabanoğlu, Samiye; Yelekçi, Kemal; Temel, Hamdi; Paşa, Salih; Ezer, Nurten; Çalış, Ihsan; Uçar, Gülberk
The inhibitory effects of flavonoids on monoamine oxidases (MAOs) have attracted great interest since alterations in monoaminergic transmission are reported to be related to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases and psychiatric disorders such as depression and anxiety thus MAOs may be considered as targets for the treatment of these multi-factorial diseases. In the present study four Sideritis flavonoids xanthomicrol (1) isoscutellarein 7-O-[6'''-O-acetyl--d-allopyranosyl-(12)]--d-glucopyranoside (2) isoscutellarein 7-O-[6'''-O-acetyl--d-allopyranosyl-(12)]-6''-O-acetyl--d-glucopyranoside (3) and salvigenin (4) were docked computationally into the active site of the human monoamine oxidase isoforms (hMAO-A and hMAO-B) and were also investigated for their hMAO inhibitory potencies using recombinant hMAO isoenzymes. The flavonoids inhibited hMAO-A selectively and reversibly in a competitive mode. Salvigenin (4) was found to be the most potent hMAO-A inhibitor while xanthomicrol (1) appeared as the most selective hMAO-A inhibitor. The computationally obtained results were in good agreement with the corresponding experimental values. In addition the x-ray structure of xanthomicrol (1) has been shown. The current work warrants further preclinical studies to assess the potential of xanthomicrol (1) and salvigenin (4) as new selective and reversible hMAO-A inhibitors for the treatment of depression and anxiety.
Citation Count: 3
Monoamin oksidaz (MAO) inhibitör etkili yeni prazolin türevlerinin moleküler modelleme yöntemiyle tasarlanması, sentezi ve inhibisyon kinetiklerinin hesapsal ve deneysel olarak tayini
(2010) Salgın, Umut Gökşen; Erdem, Ayşe; Gökhan, Nesrin Kelekçi; Erdem, Safiye; Türkkan, Seyhan; Yelekçi, Kemal; Uçar, Gülberk
[Abstract Not Available]
Citation Count: 10
New Human Monoamine Oxidase A Inhibitors with Potential Anti- Depressant Activity: Design, Synthesis, Biological Screening and Evaluation of Pharmacological Activity
(Bentham Science, 2017) Yelekçi, Kemal; Uçar, Gülberk; Taş, Sadık Taşkın; Aksöz, Erkan; Yelekçi, Kemal; Erikçi, Açelya; Sara, Yıldırım; İskit, Alper Bektaş
Aim and objective: Depression is a momentous disease that can greatly reduce the quality of life and cause death. In depression, neurotransmitter levels such as serotonine, dopamine and noradrenaline are impaired. Monoamine oxidases (MAO) are responsible for oxidative catalysis of these monoamine neurotransmitters. Because of this relation, MAO-A inhibitors show antidepressant activity by regulating neurotransmitter levels. This study was carried out to investigate the design, synthesis and activity of new antidepressant compounds in pyrazoline and hydrazone structure. Material and method: Chalcones and hydrazides were heated under reflux to give new pyrazoline and hydrazone derivatives. Docking simulations were performed using AutoDock4.2. hMAO activities were determined by a fluorimetric method. To determine cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used. Behavioral activities of the three compounds were determined by using Forced Swim Test, Step-Through Passive Avoidance Test, Elevated Plus Maze and Open Field Arena Tests. Results: According to in vitro tests, all of the synthesized compounds were found more potent than moclobemide and six of the synthesized compounds were found more selective than moclobemide. Three of the synthesized compounds were investigated for their behavioral activities comparing with moclobemide after 7 days of i.p. treatment at 30 mg/kg. One of the three compounds elicited significant antidepressant properties. Conclusion: All of the synthesized compounds were found potent hMAO-A inhibitors in in vitro screening tests. Only one of the in vivo tested three compounds, (3-(2-hydroxy-5-methylphenyl)-5- p-tolyl-4,5-dihydropyrazol-1-yl)(pyridin-4-yl) methanone indicated significant antidepressant activity. This article opens a window for further development of new pyrazoline and hydrazone derivatives as antidepressant agents.
Citation Count: 123
New pyrazoline bearing 4(3H)-quinazolinone inhibitors of monoamine oxidase: Synthesis biological evaluation and structural determinants of MAO-A and MAO-B selectivity
(Pergamon-Elsevier Science Ltd, 2009) Yelekçi, Kemal; Koyunoğlu, Semra; Yabanoğlu-Çiftçi, Samiye; Yelekçi, Kemal; Özgen, Özen; Uçar, Gülberk; Erol, Kevser; Kendi, Engin; Yeşilada, Akguel; Yelekçi, Kemal
A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a-4h 4j-4n and 5g-5l) and the MAO-B (compounds 4i and 5a-5f) isoforms. However none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i 4k 5e 5i and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343 as well as pi-pi stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound which was greater in the complex of MAO-A-4i as compared to the corresponding MAO-B complex. (C) 2008 Elsevier Ltd. All rights reserved.
Citation Count: 33
Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors
(Pergamon-Elsevier Science Ltd, 2009) Yelekçi, Kemal; Şimşek, O. Özgün; Ercan, Ayşe; Yelekçi, Kemal; Şahin, Z. Sibel; Işık, Şamil; Uçar, Gülberk; Bilgin, Abdullah Altan
A novel series of 2-thiocarbamoyl-234567-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-33a 4567-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR H-1 NMR C-13 NMR D-2 NMR DEPT EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d 1e 2c 2d 2e) and the MAO-B (compounds 1a 1b 1c 2a 2b) isoforms. In the discussion of the results the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds carrying N-allyl and N-phenyl appeared to select the MAO-A isoform. The inhibition pro. le was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a 1d 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K-i values were obtained. In the docking of the MAO-A complex the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However it binds slightly weaker (experimental K-i = 1.23 mu M) to MAO-B than to MAO-A (experimental K-i = 4.22 nM). (C) 2009 Elsevier Ltd. All rights reserved.
Citation Count: 20
Synthesis and Screening of Human Monoamine Oxidase-A Inhibitor Effect of New 2-Pyrazoline and Hydrazone Derivatives
(Wiley-VCH Verlag GmbH, 2015) Yelekçi, Kemal; Baysal, İpek; Yabanoğlu-Çiftçi, Samiye; Djikic, Teodora; Yelekçi, Kemal; Uçar, Gülberk; Ertan, Rahmiye
A group of 35-diaryl-2-pyrazoline and hydrazone derivatives was prepared via the reaction of various chalcones with hydrazide compounds in ethanol. Twenty original compounds were synthesized. Ten of these original compounds have a pyrazoline structure nine of these original compounds have a hydrazone structure and one of these original compounds has a chalcone structure. Structural elucidation of the compounds was performed by IR H-1 NMR C-13 NMR mass spectral data and elemental analyses. These compounds were tested for their inhibitory activities toward the A and B isoforms of human monoamine oxidase (MAO). Except for 3k and 6c all compounds were found to be competitive reversible and selective inhibitors for either one of the isoforms (hMAO-A or MAO-B). Compounds 3k and 6c were found to be competitive reversible but non-selective MAO inhibitors. Compound 6h showed hMAO-B inhibitory activity whereas the others potently inhibited hMAO-A. Compound 5c showed higher selectivity than the standard drug moclobemide. According to the experimental K-i values compounds 6i 6d and 6a exhibited the highest inhibitory activity toward hMAO-A. The AutoDock 4.2 program was employed to perform automated molecular docking. The calculated results obtained computationally were in good agreement with the experimental values.