Krzysztof Sztanke

An insight into synthetic Schiff bases revealing antiproliferative activities in vitro

Schiff bases or azomethines are among the most important groups of biomolecules. These compounds have been found to reveal both remarkable biological activities and a variety of valuable practical applications. An interest in the exploration of novel series of synthetic Schiff bases has undoubtedly been growing due to their proven utility as attractive lead structures for the design of novel cytotoxic and cytostatic agents with a mechanism of action that sometimes differs from that of clinically authorized anticancer agents. Therefore, in the present paper we have focussed our attention on the collected synthetic simple Schiff bases of aldimine- and ketimine-types revealing anticancer activities in vitro, that have been described in the scientific literature during the last decade, and on structural variations whose affect the antiproliferative activity in sets of the designed molecules.

Volatile Anesthetics Reduce Biochemical Markers of Brain Injury and Brain Magnesium Disorders in Patients Undergoing Coronary Artery Bypass Graft Surgery

OBJECTIVES Neuropsychological disorders are some of the most common complications of coronary artery bypass graft (CABG) surgery. The early diagnosis of postoperative brain damage is difficult and mainly based on the observation of specific brain injury markers. The aim of this study was to analyze the effects of volatile anesthesia (VA) on plasma total and ionized arteriovenous magnesium concentrations in the brain circulation (a-vtMg and a-viMg), plasma matrix metalloproteinase-9 (MMP-9), and glial fibrillary acidic protein (GFAP) in adult patients undergoing CABG surgery. DESIGN An observational study. SETTING The Department of Cardiac Surgery in a Medical University Hospital. PATIENTS AND METHODS Studied parameters were measured during surgery and in the early postoperative period. Patients were assigned to 3 groups: group O, patients who did not receive VA; group ISO, patients who received isoflurane; and group SEV, patients who received sevoflurane. RESULTS Ninety-two patients were examined. CABG surgery increased MMP-9 and GFAP. The highest MMP-9, GFAP, and the most dramatic disorders in a-vtMg and a-viMg were noted in group O. CONCLUSIONS Cardiac surgery increased plasma MMP-9 and GFAP concentrations. Changes in MMP-9, GFAP, and arteriovenous tMg and iMg were significantly higher in group O. Volatile anesthetics, such as ISO or SEV, reduced plasma MMP-9, GFAP concentrations, and disturbances in a-vtMg and a-viMg.

Crystal structure, antitumour and antimetastatic activities of disubstituted fused 1,2,4-triazinones

Molecular structure of 3,8-disubstituted 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones (8-14) was confirmed by X-ray crystallography of 14. All the compounds were evaluated for their antitumour and antimetastatic activities in vitro. Furthermore, their cytotoxicities towards human normal cell line-HSF cells were established, allowing us to point out some structure-activity relationships. Among them, imidazotriazinone 12, revealing remarkable dose-dependent viability decreases in human myeloma RPMI 8226 cells, was found to be completely non-toxic towards normal HSF cells. In addition, heterobicycles 8-12 were proved to exhibit significant antimetastatic potentials in the motility assay.

Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds

Reversed-phase liquid chromatography (RPLC) with different stationary phases, i.e., octadecylsilyl, immobilized artificial membrane and immobilized cholesterol, was used to study lipophilicity of 56 newly-designed 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones and 2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones with potential anti-proliferative, anti-metastatic and analgesic activities. Extrapolated retention parameters that correspond to pure buffer as the mobile phase, i.e., logkw values are used as chromatographic lipophilicities. The lipophilic properties of compounds also are characterized by computed logP values and basic pharmacokinetic descriptors calculated in silico with the use of ACD/Percepta software according to Abrahams linear solvation energy relationship. Chromatographic and partitioning parameters are compared with biological descriptors using principal component analysis (PCA), and similarities and dissimilarities between variables and compounds are described. Highly significant, predictive relationships between biological descriptors and chromatographic parameters are obtained. Reversed parabolic relationships, which have very good statistical quality between various biological descriptors, i.e., logKsc, logKp, logBB, and logKhsa, and the logkw values, indicate the advantages of a cholesterol column in comparison with immobilized artificial membrane and octadecylsilyl stationary phase.

Synthesis, structure elucidation, determination of the lipophilicity and identification of antitumour activities in vitro of novel 3-(2-furanyl)-8-aryl-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones with a low cytotoxicity towards normal human skin fibroblast cells

Eleven novel 3-(2-furanyl)-8-aryl-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones (12-22) were designed and obtained from appropriate 1-aryl-2-hydrazonoimidazolidines (1-11) by condensation reaction with 2-oxo-2-furanacetic acid and subsequent cyclocondensation of intermediate chain derivatives. IR, (1)H NMR and (13)C NMR spectra and elemental analyses confirmed the chemical structure of all the synthesized compounds. The reversed-phase HPLC method was optimized and proved to be applicable and reliable for the analysis of these unknown small molecules (12-22). These compounds were chromatographed on octadecyl silica (ODS) stationary phase and their hydrophobic parameters expressed as the log k(w) values were determined by RP-HPLC, using mixtures of methanol and water as mobile phases with different methanol concentrations. Octane-1-sulfonic acid sodium salt (OSA-Na) and 20% acetate buffer (pH 3.5) was added to the mobile phase (eluent containing 0.01 M/L OSA-Na in organic modifier (MeOH)-buffered mobile phase). The high values of regression coefficients (r >0.9841) for all the compounds investigated proved the excellent fit between experimental data and the Snyder-Soczewiński equation. Results obtained from the reversed-phase HPLC were compared both with those theoretically calculated and with those obtained from an ALOGPS 2.1. software by the use of nine different computational methods for estimation of log P. The predicted values of log P by use of AB log P algorithm revealed the best correlation with the experimental log k(w) values for the investigated solutes, since a good correlation (r=0.7760) between these quantities was found. The majority of novel imidazotriazinones were found to be evidently effective in vitro against human cancerous cells (HeLa and T47D) in an effective concentration of 50 μg/mL. Five compounds (13, 15, 16, 18 and 22) revealed remarkable antiproliferative activities and selective cytotoxicities for cancer cells over normal HSF cells. Therefore these ones may be considered as a basis for the design of novel useful non-toxic (13, 15 and 16) and low toxic (18 and 22) anticancer agents.

A novel fused 1,2,4-triazine aryl derivative as antioxidant and nonselective antagonist of adenosine A2A receptors in ethanol-activated liver stellate cells

It has been detected that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. In this paper we examined if our new triazine derivative (IMT) can inhibit ethanol-induced activation of HSCs measured as increased α-SMA, collagen synthesis and enhanced oxidative stress in rat liver stellate cells. We also investigated its influence on cytokines (TGF-β, TNF-α) synthesis, MMP-2 and TIMP-1 production and ethanol-induced intracellular signal transduction. Moreover, with using of known adenosine A(2A) receptor agonist (CGS 21680), and antagonist (SCH 58261) we examined if this triazine derivative acts on adenosine receptors. We detected a strong antagonistic action of new triazine derivative (IMT) on ethanol-induced rat liver stellate cells activation, observed as a significant decrease in α-SMA, collagen synthesis, reactive oxygen species production, TGF-β, TNF-α, MMP-2 and TIMP-1 production as well as JNK, p38MAPK, NFκB, IκB, Smad3 phosphorylation. Moreover, IMT strongly inhibited activation of stellate cells by known selective agonist of adenosine A(2A) receptor (CGS 21680). When known A(2A) receptor antagonist (SCH 58261) was used together with IMT this effect was not spectacular. Additionally, only slight enhancement of inhibition was observed when cells were pretreated both IMT with SCH 58261, hence we suppose that IMT acts as nonselective antagonist of A(2A) receptors, and, besides its antioxidant activity, also by this way inhibited ethanol-induced stellate cell activation.

Lipophilicity of novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione derivatives determined by reversed-phase HPLC and computational methods

Eight novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones (1-8) have been obtained as a bioactive set of substances and their lipophilicity has been studied. The logk values of fifteen reference compounds and eight newly synthesised imidazotriazine-3,4-dione derivatives were determined by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol and water as mobile phases with different methanol concentrations. The relationships between logk values of a set of reference compounds (fifteen compounds) and investigated ones (eight compounds) and concentration of methanol was used for determination of the logkwater values by extrapolation. The partition coefficients (logP) values for reference compounds measured experimentally were taken from the literature. The calibration equation was then obtained for the standards of known lipophilicity (logPHPLC) and logkwater. In next step the partition coefficients of new synthesised solutes were calculated from the calibration equation. For the comparison purpose, additionally the partition coefficients (logPcalc.) of the examined imidazotriazine-3,4-diones were calculated by means of the Pallas 3.1.1.2. software. It was found that logkwater values as a lipophilicity measure of derivatives correlate well with partition coefficients measured experimentally (logPHPLC). Correlation between the logPHPLC and the logarithm of partition coefficient calculated by Pallas software (logPcalc.) is not so satisfactory as that for values determined experimentally. Furthermore, it has been found that the lipophilicity variation of investigated imidazotriazine-3,4-diones (1-8) correlates well with their acute toxicity expressed as log(1/LD50). The drug-likeness of all the bioactive 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones was assessed on the basis of their structural properties by applying Lipniskis rule of five. The solutes have all four parameters important for the favourable pharmacokinetics in the human body that would make them likely orally active drugs in humans.

Retention Data for Some Carbonyl Derivatives of Imidazo(2,1-c)(1,2,4)triazine in Reversed-Phase Systems in TLC and HPLC and their Use for Determination of Lipophilicity. Part 1. Lipophilicity of 8-Aryl-3-phenyl-6,7- dihydro-4H-imidazo(2,1-c)(1,2,4)triazin-4-ones

Thirteen carbonyl derivatives of imidazo [2,1-c][1,2,4]triazine have been synthesized as a new bioactive set of substances. Investigations of chromatographic retention with use of mobile phases containing different concentrations of modifier enable derivation of several characteristics indicative of lipophilicity differences among the compounds. The lipophilicity (RMW) of the solutes was determined by reversed-phase thin-layer chromatography (RP TLC) with aqueous mobile-phases containing organic modifiers (methanol or dioxane) on water-wettable octadecyl silica. Reversed-phase high-performance liquid chromatography (RP HPLC) systems with aqueous mobile phases and different organic modifiers (methanol, dioxane, acetonitrile, tetrahydrofuran) on octadecyl silica columns was also used for determination of the lipophilicity (log kw) of the thirteen derivatives. Correlations between ϕ0 (MeOH) values and ϕ0 (modifier) were established for all the compounds with high values of correlation coefficients (r > 0.93).

Synthesis, structure elucidation and identification of antiproliferative activities of a novel class of thiophene bioisosteres bearing the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold.

The straightforward and practical synthesis route and remarkable antitumour activities in vitro of a novel class of thiophene bioisosteres (10-18) are disclosed. These molecules were obtained with good overall yields via the reaction of 1-aryl-2-hydrazonoimidazolidine hydroiodides with ethyl 2-oxo-2-(2-thienyl)acetate in the presence of triethylamine in refluxing DMF/methanol mixture. All the synthesized compounds proved to be markedly effective against human tumour cells: A549, HeLa, T47D and TOV112D and more cytotoxic than pemetrexed against A549, HeLa and T47D cells. Among these strongly antiproliferative active molecules, the disclosed three thiophene bioisosteres (11, 17 and 18) are proposed as the most promising anticancer lead structures for the rational design of more selective antitumour agents because they proved to be markedly lower cytotoxic towards normal than tumour cells. Results from the bioassay based on a double fluorochrome staining were worthy to be described because they provide a clue to the mode of action of one (18) of the most promising anticancer lead structures of the series.

Synthesis, structure elucidation and in vitro anticancer activities of novel derivatives of diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinate and ethyl (4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetate

The worked out and optimized synthesis routes and remarkable antitumour activities in vitro of novel polynitrogenated derivatives of diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinate (7-10) and ethyl (4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetate (11-16) are presented. Small molecules based on the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold (11-16) were obtained with fairly modest to good overall yields by very facile addition reactions of the nucleophilic centred 1-aryl-2-hydrazonoimidazolidine hydroiodides to diethyl acetylenedicarboxylate (DEAD) in the presence of triethylamine (TEA) and a subsequent cyclocondensation of the putative intermediate chain hydrazones. Heterobicyclic products 12 and 14-16 could also be prepared in high overall yields by an effective intramolecular cyclocondensation of the isolated stable and antiproliferative active heterocyclic hydrazones, namely, diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinates (7-10), performed in refluxing DMF. These intermediates are the first products to be formed in the result of an addition of the nucleophilic reactants, namely, 1-aryl-2-hydrazonoimidazolidines of the 1-6 type, bearing the basic nitrogen atom of the hydrazono moiety (N-NH2), to the carbon-carbon triple bond of the highly electrophilic alkyne, that is, DEAD. Molecular structures of the synthesized compounds (7-16) in the DMSO-d6 solutions were verified by (1)H NMR and (13)C NMR spectral data. These were finally confirmed based on the advanced 2D HMBC and HMQC NMR experiments, which were performed for the two representatives (8 and 11) of the two synthesized sets of the bioactive substances. Among the majority of antiproliferative active molecules, the disclosed herein ethyl [4-oxo-8-(3-chlorophenyl)-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (14) is proposed as a promising lead structure for the design of novel highly selective antitumour agents because of the distinctly marked lower cytotoxicity towards the primary cell line of normal HSF cells and several-fold higher against cancer cells used. A double fluorochrome mix-staining was performed in order to find out about the possible mode of action by which this novel small heterobicycle reveals remarkable antiproliferative effects in vitro. Taking into account the obtained double staining results, this small molecule was identified as capable of inducing significantly higher levels of necrotic cells in human cancer cell lines (T47D and HeLa) than in normal HSF cells. Furthermore, its cytotoxicity against cells was found to be connected to the predominant induction of necrosis over apoptosis.