Preliminarno ispitivanje antimikotskog i citotoksičnog djelovanja derivata cikloalkil[b]tiofena PLS-DA analizom

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcusneoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). Forantiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and forantiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA)applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.Koristeći supstituirane aromatske aldehide u Gewaldovim aduktima 1a-c sintetizirani su derivati 2-[(ariliden)amino]-cikloalkil[b]tiofen-3-karbonitrila (2a-x). Ispitano je antimikotsko djelovanje tih spojeva na gljivice Candida krusei i Criptococcus neoformans te antiproliferativno djelovanje na tri humane tumorske stanične linije (HT29, NCI H-292 i HEP). Za antiproliferativno djelovanje primijenjena je metoda parcijalnih najmanjih kvadrata (PLS) koristeći softverski program Pentacle. Neki od ispitanih spojeva pokazuju obećavajuće antimikotsko i antiproliferativno djelovanje. Najjače antimikotsko djelovanje imaju cikloheksil[b]tiofen derivati, a najjače antiproliferativno djelovanje cikloheptil[b]tiofen derivati, posebice 2-[(1H-indol-2-il-metiliden)amino]-5,6,7,8-tetrahidro-4H-ciklohepta[b]tiofen-3-karbonitril (2r), koji inhibira više od 97 % rast svih triju ispitivanih staničnih linija. Primijenjena PLS diskriminirajuća analiza dala je dobre istraživačke i prognostičke rezultate i pokazala da deskriptori dobro koreliraju s biološkim rezultatima

The Distribution of Ottoman and Öztürkçe Synonyms in Contemporary Turkish

Thesis is dedicated to the manifestation of the Turkish language reform using the methods od corpus linguistics. Aim of the thesis is to find out for the selected pairs of original Ottoman words and their Turkish equivalents to what extent are both variant sused in contemporary Turkish texts and to assess if any of the pairs was not functionally differentiated and if the choice was influenced by any contextual factors. In the thesis, we examine the frequency of adjectives, whether one of the variants is more or less used; Ottoman variants are used more often. In the case of pairs, we examine the frequency and preference of variants in types of text, in most cases one variant is preferred in all types of text, but some of them were differentiated. In the case of the pair siyasal and siyasi, on 500 randomly generated sentences, we examine possessors and adjective suffixes in the sentence bound to the possessor, as well as adjectives with the suffix -sel and -i, which are not bound to it and are in the sentence. In the first case, in most cases, the suffixes are matching, in the second case, there suffixes are matching with the word siyasal, but not with the word siyasi. Key words Turkish language reform, corpus linguistics, adjective suffix -sel, adjective suffix -i, language purismPráca sa venuje prejavom tureckej jazykovej reformy v súčasnej turečtine s využitím metód korpusovej lingvistiky. Cieľom práce je pre vybrané dvojice pôvodných osmanských slov a ich tureckých ekvivalentov zistiť, do akej miery sú oba varianty používané v súčasných tureckých textoch a vyhodnotiť, či u niektorej z dvojíc nedošlo k funkčnému rozrôzneniu, a či voľba je ovplyvnená niektorými kontextovými faktormi. V práci skúmame frekventovanosť adjektív, či je jeden z variantov viac alebo menej používaný, častejšie sú používané osmanské varianty. Pri dvojiciach skúmame frekvenciu a preferenciu variant v druhoch textu, u väčšiny je preferovaný vo všetkých typoch textu jeden variant, ale došlo aj k rozrôzneniu. Pri dvojici siyasal a siyasi skúmame na 500 náhodne generovaných vetách riadiace substantíva a prípony prívlastkov vo vete viažuce sa na riadiace substantívum a tiež na prívlastky s príponou -sel a -i, ktoré sa na neho neviažu a sú vo vete. V prvom prípade dochádza vo väčšine prípadov ku zhode v prípone, v druhom prípade dochádza ku zhode prípony pri slove siyasal, nedochádza však pri slove siyasi. Kľúčové slová Turecká jazyková reforma, korpusová lingvistika, adjektívny sufix - sel, adjektívny sufix -i, jazykový purizmusDepartment of Middle Eastern StudiesKatedra Blízkého východuFilozofická fakultaFaculty of Art

The Distribution of Ottoman and Öztürkçe Synonyms in Contemporary Turkish

Thesis is dedicated to the manifestation of the Turkish language reform using the methods od corpus linguistics. Aim of the thesis is to find out for the selected pairs of original Ottoman words and their Turkish equivalents to what extent are both variant sused in contemporary Turkish texts and to assess if any of the pairs was not functionally differentiated and if the choice was influenced by any contextual factors. In the thesis, we examine the frequency of adjectives, whether one of the variants is more or less used; Ottoman variants are used more often. In the case of pairs, we examine the frequency and preference of variants in types of text, in most cases one variant is preferred in all types of text, but some of them were differentiated. In the case of the pair siyasal and siyasi, on 500 randomly generated sentences, we examine possessors and adjective suffixes in the sentence bound to the possessor, as well as adjectives with the suffix -sel and -i, which are not bound to it and are in the sentence. In the first case, in most cases, the suffixes are matching, in the second case, there suffixes are matching with the word siyasal, but not with the word siyasi. Key words Turkish language reform, corpus linguistics, adjective suffix -sel, adjective suffix -i, language puris

Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I: Synthesis, Biological Evaluation and Molecular Docking Study

A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a–17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81–9.03 × 104 M−1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a–17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a–17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7–GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR–GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e–17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives

Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines

A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a–2c) in order to test the compounds’ ability to inhibit both cancer cell growth and topoisomerase I and II activity. The ability of human topoisomerase I (hTOPI) and II to relax supercoiled plasmid DNA in the presence of various concentrations of the tacrine-coumarin hybrid molecules was studied with agarose gel electrophoresis. The biological activities of the derivatives were studied using MTT assays, clonogenic assays, cell cycle analysis and quantification of cell number and viability. The content and localization of the derivatives in the cells were analysed using flow cytometry and confocal microscopy. All of the studied compounds were found to have inhibited topoisomerase I activity completely. The effect of the tacrine-coumarin hybrid compounds on cancer cells is likely to be dependent on the length of the chain between the tacrine and coumarin moieties (1c, 1d = tacrine-(CH2)8–9-coumarin). The most active of the tested compounds, derivatives 1c and 1d, both display longer chains

Acridine Based N-Acylhydrazone Derivatives as Potential Anticancer Agents: Synthesis, Characterization and ctDNA/HSA Spectroscopic Binding Properties

A series of novel acridine N-acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on proliferation of A549 and CCD-18Co have been evaluated. The acridine-DNA complex 3b (-F) displayed the highest Kb value (Kb = 3.18 × 103 M−1). The HSA-derivatives interactions were studied by fluorescence quenching spectra. This method was used for the calculation of characteristic binding parameters. In the presence of warfarin, the binding constant values were found to decrease (KSV = 2.26 M−1, Kb = 2.54 M−1), suggesting that derivative 3a could bind to HSA at Sudlow site I. The effect of tested derivatives on metabolic activity of A549 cells evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assay decreased as follows 3b(-F) > 3a(-H) > 3c(-Cl) > 3d(-Br). The derivatives 3c and 3d in vitro act as potential dual inhibitors of hTopo I and II with a partial effect on the metabolic activity of cancer cells A594. The acridine-benzohydrazides 3a and 3c reduced the clonogenic ability of A549 cells by 72% or 74%, respectively. The general results of the study suggest that the novel compounds show potential for future development as anticancer agents