Person: ZENGİN KURT, BELMA
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Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors
New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.
Synthesis, Biological Activity and Multiscale Molecular Modeling Studies for Coumaryl-carboxamide Derivatives as Selective Carbonic Anhydrase IX Inhibitors
New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms.
Tail-Approach-Based Design and Synthesis of Coumarin-Monoterpenes as Carbonic Anhydrase Inhibitors and Anticancer Agents
In this study, sixty novel coumarin-monoterpene compounds were synthesized in two series [thirty-two compounds (12-43) bearing a triazole ring in the first series, and twenty-eight compounds (44-71) bearing an alkyl chain in the second one]. Their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I, II, IX, and XII and anticancer potentials were determined. All synthesized molecules selectively inhibited CA IX and XII. 23 and 42 were found to be the strongest inhibitors, with K i values of 1.9 nM against hCA IX. Also, 70 showed the highest inhibitory activity with a K i value of 4.9 nM against hCA XII. Moreover, their cytotoxic effects on colon adenocarcinoma (HT-29), prostate adenocarcinoma (PC-3), and breast adenocarcinoma (MCF-7) cell lines were evaluated. According to the cytotoxicity results, 14 (IC50 = 2.48 μM) and 63 (IC50 = 3.91 μM) exhibited the highest cytotoxicity on the MCF-7 cells, while 23 showed the strongest cytotoxic effect on both PC-3 (IC50 = 9.40 μM) and HT-29 (IC50 = 12.10 μM) cell lines. 14, 23, and 66 decreased CA IX and CA XII protein expression in HT-29 cells, while 23 and 66 showed the strongest reduction of both CA IX and CA XII in MCF-7 cells. All of the selected compounds increased total apoptosis in a concentration-dependent manner in HT-29 and MCF-7 cells. 14 has the strongest apoptotic effect in MCF-7 cells. 23 increased early apoptosis primarily, while 14 and 66 increased total apoptosis in HT-29. In addition, PI/Hoechst staining proves that apoptotic cells are increased in HT-29 with an effect of 14, 23, and 66. As a result of the modeling studies, it has been shown that only the open coumarin form of the compounds can interact directly with the active-site Zn2+ ion. It has been shown that coumarin-monoterpene structures with different alkyl and monoterpene groups both specifically inhibit CA IX and XII and exhibit specific cytotoxicity in different cell lines.
Structural and mechanical analysis of three orthodontic adhesive composites cured with different light units
Objective: To evaluate the effects of three different curing units on the physical and mechanical features of three different orthodontic adhesive resin materials. Material and Methods: 45 specimens (5 mm in diameter, and 2 mm in thickness) of each of the three different adhesive composite resin materials (Transbond XT, Grēngloo™ Adhesive and Light Bond Paste) were cured with three different light units (a polywave third generation (Valo), a monowave (DemiUltra), and a second-generation LED (Optima 10)). To quantify degree of conversion (DC), the Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy was used in transmission mode (ALPHA FT-IR Spectrometer, Bruker Optics, Germany). Vickers hardness value was recorded under constant load 100 g for 10 s with a microhardness tester (HMV M-1, Shimadzu Corp., Kyoto, Japan). The data were statistically analyzed using Kruskal-Wallis and chi-square tests. The level of significance was considered p<0.05. Results: The highest DC values were obtained as a result of curing with Optima 10. This rate was followed by Demi Ultra and Valo, respectively. Transbond XT samples showed a lower level of conversion than the samples of Light Bond Paste and Grēngloo™ Adhesive. The top surfaces of each material showed higher hardness values than the bottom surfaces (p<0.05). The Light Bond Paste showed the highest hardness values both on the top and bottom surfaces among the three materials, followed by Grēngloo™ Adhesive. While the hardness values of the top surfaces of the samples cured with Demi Ultra and Valo light units were similar, higher hardness values are recorded with Valo on the bottom surfaces (Valo; 85.200/75.200 (top/bottom) versus Demi Ultra; 86.100/66.000 (top/bottom)). Conclusions: The different DC and the surface hardness properties were recorded for the resin as orthodontic adhesives depending on different light units. Shorter radiation time caused lower DC and surface hardness values.
New Schiff bases based on isatin and (thio)/carbohydrazone: preparation, experimental–theoretical spectroscopic characterization, and DFT approach to antioxidant characteristics
© 2022, The Author(s), under exclusive licence to Springer Nature B.V.In this study, synthesis, spectroscopic elucidation, and investigation of antioxidant properties of new Schiff bases based on isatin and (thio)/carbohydrazone derivatives have been reported for the first time. The structures of the synthesized compounds were elucidated by FT-IR, 1H-NMR, and 13C-NMR spectroscopic methods and elemental analysis. Their DPPH, ABTS, and CUPRAC activities were evaluated as antioxidant properties. Electronic and spectral data of the compounds were obtained by DFT calculations at the B3LYP/6–311+ +G(2d,2p) level of theory. Intramolecular interactions and charge densities on the bonds were analyzed by QTAIM and IRI calculations. In addition to parameters such as frontier molecular orbital energy eigenvalues, electronegativity, nucleophilicity index, and electrodonating power, the changes in the enthalpy of the compounds for the reactions realized through the SET mechanism were calculated to elucidate the antioxidant reactions of the compounds. Most of synthesized compounds exhibited antioxidant activities with the IC50 values ranging from 27.13 to 43.35 µM for DPPH, from 6.47 to 24.96 µM for ABTS and with the A0.50 values ranging from 9.04 to 47.52 µM for CUPRAC. Among them, compound 3, containing two hydroxyl groups, showed the strongest antioxidant activity for each assay (IC50 = 27.13 µM for DPPH, 6.47 µM for ABTS, and A0.50 = 9.04 µM for CUPRAC). The antioxidant activities of compound 3 were almost two or threefold weaker than that of BHA (IC50 = 9.55 µM for DPPH, 3.42 µM for ABTS, and A0.50 = 2.24 µM for CUPRAC), used as a standard. In addition, thiocarbohydrazone compounds exhibited higher antioxidant activity than carbohydrazones. Electron donating ability and single electron transfer enthalpy calculations predicted that thiocarbohydrazone compounds can perform SET reactions more easily than carbohydrazones.
Synthesis of Sorafenib−Ruthenium Complexes, Investigation of Biological Activities and Applications in Drug Delivery Systems as an Anticancer Agent
Anticholinesterase, antioxidant, antiaflatoxigenic activities of ten edible wild plants from Ordu area, Turkey
Turkey has highly rich floras of medicinal and aromatic plants because of having various climate conditions in different regions. One of these regions is Middle Black Sea Region, especially Ordu Province. Extracts of 10 edible plants (Arum maculatum L., Hypericum orientale L., Ornithogalum sigmoideum Freyn et Sint., Silene vulgaris Garcke var. macrocarpa, Plantago lanceolata L., Achillea millefolium L. subsp. pannonica, Rumex crispus L., Rumex acetosella L., Capsella bursa-pastoris L., Coronopus squamatus Asch.), grown in Ordu, Turkey, were prepared with different solvents (hexane, ethanol and water, separately) and their anticholinestrase and antiaflatoxigenic activities were evaluated. Additionally, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the extracts were assayed. The ethanol extract of R. acetosella exhibited the highest antioxidant activity (A0.5 value of 25.31 µg/mL, for CUPRAC activity; IC50 value of 23.73 µg/mL, for ABTS activity). The hexane extract of C. bursa-pastoris showed the strongest inhibition against AChE enzyme with IC50 value of 7.24 µg/mL, and the hexane extract of A. millefolium subsp. pannonica had the highest BChE activity with IC50 value of 6.40 µg/mL. The ethanol extract of P. lanceolata exhibited the strongest inhibition against aflatoxin with 88% inhibition.
Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies
Totally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 μM against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the Ki value was calculated as 36.3 μM. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 μM) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 μM) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 μM strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.