Gülşen Akalın Çiftçi

Synthesis and Biological Evaluation of Some 1,2‐Disubstituted Benzimidazole Derivatives as New Potential Anticancer Agents

The synthesis of some new 1‐(2‐aryl‐2‐oxoethyl)‐2‐[(morpholine‐4‐yl)thioxomethyl]benzimidazole derivatives and investigation of their anticancer activities were the aims of this work. 2‐(Chloromethyl)benzimidazole compound was reacted with sulfur and morpholine via Willgerodt–Kindler reaction to give 2‐[(morpholine‐4‐yl)thioxomethyl]benzimidazole. Then, the obtained compound was reacted with appropriate α‐bromoacetophenone derivatives in the presence of potassium carbonate to give the final products. Structure elucidation of the final compounds was achieved by FT‐IR, 1H NMR spectroscopy and MS spectrometry. The anticancer activities of the final compounds were evaluated by MTT assay, BrdU method, and flow cytometric analysis on C6, MCF‐7, and A549 tumor cells. Most of the synthesized compounds exhibited considerable selectivity against the MCF‐7 and C6 cell lines.

Escin reduces cell proliferation and induces apoptosis on glioma and lung adenocarcinoma cell lines

Aesculus hippocastanum (the horse chestnut) seed extract has a wide variety of biochemical and pharmacological effects including anti-inflammatory, antianalgesic, and antipyretic activities. The main active compound of this plant is escin. It is known that several medicinal herbs with anti-inflammatory properties have been found to have a role in the prevention and treatment of cancer. In the present study, the cytotoxic effects of escin in the C6 glioma and A549 cell lines were analyzed by MTT. Apoptotic effects of escin on both cell lines were evaluated by Annexin V binding capacity with flow cytometric analysis. Structural and ultrastructural changes were also evaluated using transmission electron microscopy. The results indicated that escin has potent antiproliferative effects against C6 glioma and A549 cells. These effects are both dose and time dependent. Taken together, escin possesses cell cycle arrest on G0/G1 phase and selective apoptotic activity on A549 cells as indicated by increased Annexin V-binding capacity, bax protein expression, caspase-3 activity and morphological changes obtained from micrographs by transmission electron microscopy.

Synthesis and Biological Evaluation of Some Pyrazoline Derivatives Bearing a Dithiocarbamate Moiety as New Cholinesterase Inhibitors

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1‐(chloroacetyl)‐3‐(2‐furyl)‐5‐aryl‐2‐pyrazolines with sodium salts of N,N‐disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellmans spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17, when compared with eserine. Compounds effective on AChE carry the 2‐dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2‐dimethylaminoethyl and 3,4‐methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.

Synthesis and antiproliferative activity of new 1,5-disubstituted tetrazoles bearing hydrazone moiety

A new class of tetrazole-hydrazone derivatives including chloro-substituted phenyl moiety were synthesized to perform anticancer activity screening. The structural elucidation of the compounds was performed by IR, 1H NMR, 13C NMR, MS spectral, and elemental analyses data. Anticancer effect of the compounds was evaluated against A549 and C6 tumor cell lines. MTT, analysis of DNA synthesis and analysis of caspase-3 activation assays were carried out for anticancer activity investigations. Compounds N′-(2-chlorobenzylidene)-4-[(1-phenyl-1H-tetrazole-5-yl)thio]butanohydrazide (3a),N′-(2,3-dichlorobenzylidene)-4-[(1-phenyl-1H-tetrazole-5-yl)thio]butanohydrazide (3d), and N′-(3,4-dichlorobenzylidene)-4-[(1-phenyl-1H-tetrazole-5-yl)thio]butanohydrazide (3e) showed significant anticancer activity. Anticancer screening tests also indicated that compound 3d has potential on C6 tumor cells with apoptotic pathway.

Apoptotic effects of some carbazole derivatives on lung carcinoma and glioma cell lines

In this study, we aimed to study the apoptotic effects of 2-[(9-ethyl-9H-carbazol-3-yl)amino]-2-oxoethyl N,N-disubstituted dithiocarbamates on A549 lung carcinoma and C6 glioma cell lines. Cytotoxicity analyses of DNA synthesis and detection of apoptosis by flow cytometry were evaluated to determine the anticancer activity of the compounds on both cell lines. Compounds 2, 5, and 7 which exhibited significant cytotoxic activity in MTT assay were chosen for flow cytometric analyses to determine the apoptotic percent of cells. These compounds also exhibited better DNA synthesis inhibition activity on cancer cells. Finally, acetylcholinesterase inhibition potentials of the compounds were measured. Compound 7 carrying 4-(2-dimethylaminoethyl)piperazin-1-yl moiety was the most active apoptotic agent against A549 and C6 cells. Apoptotic effect of this compound can be attributed to its AchE inhibition activity. Compounds 2 and 5 also showed apoptotic effects on C6 glioma cell lines. Compounds 2, 5, and 7 can be identified as the most promising anticancer agents against A549 and C6 cancer cell lines.

Synthesis and Evaluation of New Benzodioxole- Based Thiosemicarbazone Derivatives as Potential Antitumor Agents.

New benzodioxole-based thiosemicarbazone derivatives were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cells. In order to examine the correlation between anticancer activity and cholinesterases, the compounds were evaluated for their inhibitory effects on AChE and BuChE. The most effective anticancer agents were investigated for their effects on DNA synthesis, apoptosis and mitochondrial membrane potential. 4-(1,3-Benzodioxol-5-yl)-1-([1,1′-biphenyl]-4-ylmethylene)thiosemicarbazide (5) was identified as the most promising anticancer agent against C6 and A549 cell lines due to its inhibitory effects on C6 and A549 cells and low toxicity to NIH/3T3 cells. Compound 5 increased early and late apoptosis in A549 and C6 cells. Compound 5 also caused disturbance on mitochondrial membrane potential and showed DNA synthesis inhibitory activity in A549 and C6 cells. Compound 5 was investigated for SIRT1 inhibitory activity to provide mechanistic insight and for that purpose docking studies were also performed for this compound on SIRT1. On the other hand, compound 5 did not show any inhibitory activity against AChE and BuChE. This outcome pointed out that there is no relationship between anticancer activity of compound 5 and cholinesterases.

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by 1H NMR, 13C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman’s spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC50 = 25.5 ± 2.12 µg/mL) followed by compounds 4i (IC50 = 38.50 ± 2.12 µg/mL), 4c (IC50 = 58.42 ± 3.14 µg/mL) and 4g (IC50 = 68 ± 2.12 µg/mL) when compared with eserine (IC50 = 0.025 ± 0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC50 > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC50 = 71.67 ± 7.63 µg/mL) of compound 4e was higher than its effective dose.

Synthesis of 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and evaluation of their anticancer activity

In the present study, 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (1–6) were synthesized via the ring closure reaction of 1-(2-thienyl)-3-aryl-2-propen-1-ones with hydrazine hydrate in acetic acid. The chemical structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR and mass spectral data and elemental analyses. MTT assay, analysis of DNA synthesis and caspase-3 activation assay were carried out to determine anticancer effects of the compounds on A549 and C6 cancer cell lines. They exhibited dose-dependent anticancer activity against A549 and C6 cancer cell lines. Anticancer activity screening results revealed that compounds 1, 2 and 4 were the most potent derivatives among these compounds. But anticancer effects of these compounds may result from different death mechanisms in A549 and C6 cell lines.

Synthesis and Biological Evaluation of a New Series of Pyrazolines as New Anticandidal Agents

New pyrazoline derivatives bearing an oxadiazole moiety were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl/thienyl)-5-aryl-2-pyrazolines with 5-substituted-1,3,4-oxadiazole-2(3H)-thiones in the presence of potassium carbonate. Compounds 1 – 32 were screened for their antifungal activity against various Candida species and compared with ketoconazole. Among these compounds, the most effective derivatives were evaluated for their cytotoxicity against NIH/3T3 cells. 2-({2-[5-(4-Bromophenyl)-3-(2-furyl)-4,5-dihydro-1H-pyrazol-1-yl]-2-oxoethyl}thio)-5-(2-cyclopentylethyl)-1,3,4-oxadiazole (23) can be identified as the most potent antifungal agent against C. tropicalis due to its inhibitory effect on C. tropicalis and low toxicity to NIH/3T3 cells.

Induction of apoptosis in lung adenocarcinoma and glioma cells by some oxadiazole derivatives

Oxadiazoles have received much attention due to their wide range of biological activities including antitumor activity. In this study, we aimed to study apoptotic effects of some 1,3,4-oxadiazole derivatives on human lung adenocarcinoma (A549) and rat glioma (C6) cell lines. The cytotoxicity of the compounds on both cell lines was determined, and the effects of these compounds on DNA synthesis were measured. Compounds 2 and 6 which exhibited significant cytotoxic activity in MTT assay were chosen for flow cytometric analyses to determine apoptotic percent of cells. These compounds also exhibited better DNA synthesis inhibition activity on cancer cells. Compound 6 carrying 2,4-dichlorophenyl substituent exhibited the highest apoptotic effect on A549 cells via the induction of Caspase 3 activity. It was suggested that compounds 2 and 6 can be identified as the most promising anticancer agents against A549 and C6 cancer cell lines.