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1.
Life (Basel) ; 11(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069386

RESUMO

(1) Background: The aim of the study was to test the hypothesis that the antioxidant status in the vitreous body of eyes, which had been vitrectomized due to rhegmatogenous retinal detachment (RRD) with or without proliferative vitreoretinopathy (PVR), is higher than in eyes vitrectomized due to other retinal diseases. (2) Methods: four patient groups were analyzed: 22 eyes of patients with RRD without PVR, 27 eyes with RRD and PVR, 22 eyes with macular hole (MH) and 10 eyes with epiretinal membrane (ERM). Spectrophotometric methods were used to determine the total antioxidant status (TAS) values as well as superoxide dismutase (SOD) and glutathione reductase (GR) activities in the vitreous fluid samples. (3) Results: no significant differences in TAS values and antioxidant enzyme activities were observed among patient with RRD with and without PVR and with MH and ERM. The longer the duration of RRD leading to PVR and better postoperative visual acuity, the higher the TAS level. No significant differences were found between "macula on" and "macula off" subgroups within the RRD group and the RRD combined with PVR group. (4) Conclusions: The preliminary results do not support the thesis that the antioxidant status of vitrectomized eyes is different in patients with RRD with or without PVR in comparison to patients with MH and ERM. In patients with RRD, PVR presence and detached macula do not affect the values of TAS, SOD and GR in the vitreous fluid. The duration of the disease influences TAS in the vitreous in eyes with RRD complicated with PVR.

2.
Antioxidants (Basel) ; 10(3)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803138

RESUMO

Inflammatory bowel diseases (IBD) are a group of chronic, incurable diseases of the digestive tract, the etiology of which remains unclear to this day. IBD result in significant repercussions on the quality of patients' life. There is a continuous increase in the incidence and prevalence of IBD worldwide, and it is becoming a significant public health burden. Pharmaceuticals commonly used in IBD management, for example, mesalamine, sulfasalazine, corticosteroids, and others, expose patients to diverse, potentially detrimental side effects and frequently do not provide sufficient disease control. The chronic inflammation underlies the etiology of IBD and closely associates with oxidative/nitrosative stress and a vast generation of reactive oxygen/nitrogen species. Relative to this, several substances with antioxidant and anti-inflammatory properties are now intensively researched as possible adjunctive or independent treatment options in IBD. Representatives of several different groups, including natural and chemical compounds will be characterized in this dissertation.

3.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923942

RESUMO

The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood-brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidates. The compounds were characterized by lipophilic, structural, and electronic descriptors, i.e., chromatographic retention, topological polar surface area, polarizability, and molecular weight. Different reversed-phase liquid chromatography techniques were used to determine the chromatographic lipophilicity of the compounds that were tested, i.e., micellar liquid chromatography (MLC) with the ODS-2 column and polyoxyethylene lauryl ether (Brij 35) as the effluent component, an immobilized artificial membrane (IAM) chromatography with phosphatidylcholine column (IAM.PC.DD2) and chromatography with end-capped octadecylsilyl (ODS) column using aqueous solutions of acetonitrile as the mobile phases. Using multiple linear regression, we derived the statistically significant quantitative structure-activity relationships. All these QSAR equations were validated and were found to be very good. The investigations highlight the significance and possibilities of liquid chromatographic techniques with three different reversed-phase materials and QSARs methods in predicting the pharmacokinetic properties of our important organic compounds and reducing unethical animal testing.


Assuntos
Cromatografia de Fase Reversa/métodos , Células CACO-2 , Cromatografia Líquida/métodos , Humanos , Membranas Artificiais , Relação Quantitativa Estrutura-Atividade
4.
J Enzyme Inhib Med Chem ; 36(1): 336-344, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33390035

RESUMO

The main purpose of this investigation was to evaluate the effect of anticancer active compounds (I-VIII) on zebrafish development in order to select the safest molecules. Larval mortality, embryo hatchability and malformations were end-points used to assess the acute toxicity among embryos and larvae from compounds-/pemetrexed-treated and control groups. LC50 and MNLC (maximal non-lethal concentration) were determined. Lipophilicity-dependent structure-toxicity relationships were established. The results clearly indicated that the majority of test molecules are safe for zebrafish individuals and simultaneously are less toxic than an anticancer agent - pemetrexed. The subsequent aim of this study was to elucidate the molecular mechanism of antiproliferative activity of the most selective compounds. Substantially increased activation of caspase-6 and -8 in cancerous cell lines confirmed the proapoptotic action of molecules examined. Considering the safety for zebrafish individuals, the title compounds as inducers of apoptosis are promising drug candidates in the preclinical phase of drug development.


Assuntos
Antineoplásicos/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Fluorcarbonetos/farmacologia , Larva/efeitos dos fármacos , Triazinas/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Caspase 6/genética , Caspase 6/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Embrião não Mamífero/anormalidades , Embrião não Mamífero/metabolismo , Fluorcarbonetos/síntese química , Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Larva/metabolismo , Pemetrexede/toxicidade , Relação Estrutura-Atividade , Testes de Toxicidade , Triazinas/síntese química , Peixe-Zebra/crescimento & desenvolvimento
5.
Sensors (Basel) ; 20(18)2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32933116

RESUMO

A carbon nanofibers modified screen-printed carbon sensor (SPCE/CNFs) was applied for the determination of a novel promising anticancer agent candidate (ethyl 8-(4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3-carboxylate, EIMTC) using square-wave voltammetry (SWV). It is the first method for the quantitative determination of EIMTC. The modified screen-printed sensor exhibited excellent electrochemical activity in reducing EIMTC. The peak current of EIMTC was found to be linear in two concentration ranges of 2.0 × 10-9 - 2.0 × 10-8 mol L-1 and 2.0 × 10-8 - 2.0 × 10-7 mol L-1, with a detection limit of 5.0 × 10-10 mol L-1. The connection of flow-cell for the SPCE/CNFs with SWV detection allowed for the successful determination of EIMTC in human serum samples. Ultra-high-performance liquid chromatography coupled to electrospray ionization triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS) acted as a comparative method in the serum samples analysis.


Assuntos
Antineoplásicos , Nanofibras , Carbono , Eletrodos , Humanos , Espectrometria de Massas em Tandem
6.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979316

RESUMO

The permeation of the blood-brain barrier is a very important consideration for new drug candidate molecules. In this research, the reversed-phase liquid chromatography with different columns (Purosphere RP-18e, IAM.PC.DD2 and Cosmosil Cholester) was used to predict the penetration of the blood-brain barrier by 65 newly-synthesized drug-like compounds. The linear free energy relationships (LFERs) model (log BB = c + eE + sS + aA + bB + vV) was established for a training set of 23 congeneric biologically active azole compounds with known experimental log BB (BB = Cblood/Cbrain) values (R2 = 0.9039). The reliability and predictive potency of the model were confirmed by leave-one-out cross validation as well as leave-50%-out cross validation. Multiple linear regression (MLR) was used to develop the quantitative structure-activity relationships (QSARs) to predict the log BB values of compounds that were tested, taking into account the chromatographic lipophilicity (log kw), polarizability and topological polar surface area. The excellent statistics of the developed MLR equations (R2 > 0.8 for all columns) showed that it is possible to use the HPLC technique and retention data to produce reliable blood-brain barrier permeability models and to predict the log BB values of our pharmaceutically important molecules.


Assuntos
Antineoplásicos/química , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Analgésicos/química , Analgésicos/farmacologia , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Azóis/química , Transporte Biológico , Barreira Hematoencefálica/química , Modelos Lineares , Modelos Moleculares , Permeabilidade , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
7.
Bioorg Chem ; 95: 103480, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31864156

RESUMO

Searching for new less toxic anticancer drug candidates is a big challenge from a medical point of view. The present investigation was aimed at describing two independent synthetic approaches based on isosteric replacements, spectroscopic characteristics, in vitro anticancer and ex vivo antihaemolytic activities of novel molecules (9-22) and correlations between their standardised lipophilicity indices, computed log Paverage values and pharmacokinetic descriptors. Two novel protocols for annelation of the triazinone template on hydrazinylideneimidazolidines (1-8) (showing a high reactivity towards electrophilic reagents, such as ethyl trifluoropyruvate and ethyl 3-methyl-2-oxobutyrate) were developed for the first time, giving rise to two original classes of highly conjugated azaisocytosine-containing molecules (9-16 and 17-22). Both syntheses proceeded under basic conditions to yield the most probable intermediates (e.g. hemiaminals and imines), which in refluxing two-component solvent mixtures or a suitable solvent cyclised through closing the triazinone ring on functionalised imidazolidines in both cases. All fused azaisocytosine-containing congeners were investigated with the purpose of preselecting possible drug candidates with a better selectivity that could be suitable for further more detailed drug development studies. The majority of test molecules revealed strong antiproliferative effects in most tumour cell cultures and they were more cytotoxic against tumour cells than anticancer drug - pemetrexed. These cytotoxicities may be associated with the activation of initiator and executioner caspases (confirmed for compound 12) which are inducers of apoptosis. Simultaneously, three bioisosteres bearing the trifluoromethyl moiety at the C-3 and the ortho substitution at the phenyl ring (10, 12 and 13) proved to be the most promising in terms of selectivity as they were less or equally toxic to normal cells as pemetrexed. It was shown that isosteric replacement of the ethyl group in antitumour active congeners by the trifluoromethyl or isopropyl group was favourable for the selectivity of the designed drug-like molecules. Almost all new compounds revealed the protective effects in an ex vivo model of oxidatively stressed rat erythrocytes (better or comparable than that of ascorbic acid/Trolox), proving that they are safe to red blood cells. The statistically significant and predictive QSAR equations were derived that describe relationships between some pharmacokinetic descriptors (such as log Ka, HSA, fu, brain, Caco-2, log Kp) and lipophilicity parameters of test molecules. Among all molecules with anticancer profile, the possible drug candidates seem to be 10, 12, 13, 19 and 21 which are the least toxic for normal cells, deprived of haemolytic effects on oxidatively-stressed red blood cells and have the optimum pharmacokinetic descriptors in terms of their lipophilicity parameters. Because of a high development potential they should be utilised in further more extended in vivo investigations aimed at developing novel less toxic anticancer agents.


Assuntos
Compostos Aza/farmacologia , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Citosina/análogos & derivados , Desenho de Fármacos , Hemólise/efeitos dos fármacos , Animais , Compostos Aza/síntese química , Compostos Aza/química , Inibidores de Caspase/síntese química , Inibidores de Caspase/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citosina/síntese química , Citosina/química , Citosina/farmacologia , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Relação Estrutura-Atividade
8.
Eur J Pharm Sci ; 132: 34-43, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30807815

RESUMO

The present study was aimed at broadening the profile of toxicity and biological activity of promising fused azaisocytosine-containing congeners (I-VI) possessing medical applicability and important pharmacokinetic properties. For this purpose, the in vivo zebrafish test was applied for evaluating embryotoxic effects of test compounds, whereas the ex vivo model of oxidatively-stressed rat erythrocytes was developed for assessing their antihaemolytic activities. Additionally, the MTT-based assays suitable for assessing cytotoxic and antiviral activities of I-VI were employed. The influence of compounds I-VI on zebrafish embryos/larvae was carefully investigated in relation to lack or presence of various substituents at the phenyl moiety. The least embryotoxic proved to be the parent compound (I) and its para-methyl (II) and ortho-chloro (III) derivatives. Simultaneously, they revealed the minimum embryotoxic concentrations higher than that of aciclovir, what makes them safer than this pharmaceutic. Moreover, most of test compounds showed protective effects (better or comparable to that of ascorbic acid) on oxidatively-stressed erythrocytes. All the investigated compounds were effective at inhibiting the growth of human solid tumours of pharynx (FaDu) and tongue (SCC-25). The majority of molecules showed good selectivity indices. The most selective proved to be II showing in normal Vero cells over a 5-fold and an almost 3-fold decreased cytotoxicity relative to that in tumour SCC-25 and FaDu cells, respectively. Additionally, a 3,4-dichloro derivative (VI) was shown to possess concentration-dependent inhibitory effects on the replication of Herpes simplex virus type 1 and simultaneously at active concentrations was found to be nontoxic for normal Vero cells.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Compostos Aza/química , Citosina/análogos & derivados , Embrião não Mamífero/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Compostos Heterocíclicos de Anéis Fundidos/farmacologia , Peixe-Zebra , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Antivirais/química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Citosina/química , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Eritrócitos/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Compostos Heterocíclicos de Anéis Fundidos/química , Compostos Heterocíclicos de Anéis Fundidos/farmacocinética , Compostos Heterocíclicos de Anéis Fundidos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento
9.
Free Radic Res ; 52(6): 685-697, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29642746

RESUMO

Biologically and chemically useful hydrazinoimidazolines were evaluated as antioxidant and antihaemolytic agents. 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH•), galvinoxyl radical (GOR), nitric oxide (NO) and hydrogen peroxide (H2O2) scavenging assays, ferric ions reducing power assay, and ex vivo model of rat erythrocytes exposed to 2,2'-azobis(2-methylpropionamidine)dihydrochloride (AAPH) or H2O2 were used. The most potent DPPH• scavengers proved to be hydrazinoimidazolines 3, 2, and 4, revealing excellent antiradical effects - superior or comparable to that of all antioxidant standards used. Moreover, these molecules showed strong NO neutralising potencies - better to that of ascorbic acid (AA) (3), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) (3 and 2), butylated hydroxytoluene (BHT) (3 and 2), and butylated hydroxyanisole (BHA) (3, 2, and 4). Compound 4 was also effective in GOR scavenging. The excellent scavenger of GOR, NO, and H2O2 proved to be structure 5, with the potency superior or comparable to the majority of antioxidant standards used. In turn, compound 9 was effective in H2O2 and GOR neutralisation. All hydrazinoimidazolines revealed the reducing power that is higher than BHT. Moreover, the protective effects of most test compounds on oxidatively stressed erythrocytes were observed. Some structure-activity relationships were disclosed. A significance of the primary hydrazino group on antioxidant effects was confirmed. The most likely DPPH• and GOR scavenging mechanisms for test compounds were propound. Among all the investigated molecules, hydrazinoimidazolines 5, 3, 2, 4, and 9, due to their excellent or good antiradical activities, can represent promising antioxidant candidates with prospective utility for prevention of diseases related to reactive oxygen/nitrogen species.


Assuntos
Compostos Benzidrílicos/antagonistas & inibidores , Sequestradores de Radicais Livres/farmacologia , Hidrazinas/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Imidazolinas/farmacologia , Amidinas/antagonistas & inibidores , Amidinas/farmacologia , Animais , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Compostos Benzidrílicos/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Hidroxianisol Butilado/química , Hidroxianisol Butilado/farmacologia , Hidroxitolueno Butilado/química , Hidroxitolueno Butilado/farmacologia , Cromanos/química , Cromanos/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Sequestradores de Radicais Livres/síntese química , Hidrazinas/síntese química , Peróxido de Hidrogênio/farmacologia , Imidazolinas/síntese química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/química , Picratos/antagonistas & inibidores , Picratos/química , Ratos , Relação Estrutura-Atividade
10.
Redox Rep ; 22(6): 572-581, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28812524

RESUMO

OBJECTIVES: Two important classes of hydrazide-containing fused azaisocytosines were evaluated as possible antioxidants and characterised by UV spectroscopy. METHODS: 2,2-Diphenyl-1-picrylhydazyl (DPPH), nitric oxide (NO), hydrogen peroxide (H2O2) scavenging potencies and reducing power of molecules were evaluated. RESULTS: The strongest DPPH scavengers were found to be 9, showing the potency superior to that of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) and comparable to that of ascorbic acid (AA), and 6, revealing the antioxidant potency superior to that of BHA, BHT, PG and Trolox. In turn, 3 and 9 were the most promising NO scavengers, exhibiting the potency superior to that of BHA, BHT (3 and 9) and AA (3). The most potent H2O2 scavengers proved to be 10 and 9 showing similar or even better neutralising potency than that of Trolox, BHT and BHA. Simultaneously, the majority of hydrazides revealed higher ferric reducing abilities than that of AA and BHT. Some structure-activity relationships were explored. A possible mechanism for the DPPH radical scavenging ability of hydrazide-containing molecules was proposed. DISCUSSION: Hydrazides 3, 6 and 9 with an antioxidant potential better or comparable to that of the well-known antioxidants are proposed as new antioxidant candidates.


Assuntos
Antioxidantes/química , Ácido Ascórbico/química , Hidroxitolueno Butilado/química , Cromanos/química , Sequestradores de Radicais Livres/química , Peróxido de Hidrogênio/química , Peroxidação de Lipídeos , Galato de Propila/química , alfa-Tocoferol/química
11.
Biosens Bioelectron ; 94: 584-588, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28364705

RESUMO

The determination of ethyl [4-oxo-8-(3-chlorophenyl)-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (ETTA), a new anticancer prodrug, using adsorptive stripping voltammetry (AdSV) was described for the first time. This method is based on adsorptive/reductive behaviour of ETTA at an in situ plated bismuth film electrode (BiFE) as a sensor. A number of experimental variables (e.g., a composition and pH of the supporting electrolyte, the conditions of bismuth film deposition, an accumulation potential and time, the scan rate, etc.) were thoroughly studied in order to achieve a high sensitivity. Experimental results under optimized conditions revealed an excellent linear correlation between the monitored voltammetric peak current and the ETTA concentration in the range of 2-50µgL-1 following an accumulation time of 300s. The limit of detection (LOD) for ETTA following 300s of an accumulation time was 0.4µgL-1. The proposed facile, sensitive and inexpensive method was successfully applied to the determination of ETTA in serum. The investigated prodrug was extracted from serum using SPE method.


Assuntos
Técnicas Biossensoriais/métodos , Eletroquímica/métodos , Neoplasias/sangue , Pró-Fármacos/isolamento & purificação , Adsorção , Bismuto/química , Eletrodos , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Neoplasias/tratamento farmacológico , Pró-Fármacos/química
12.
Mol Cell Biochem ; 418(1-2): 179-88, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27334755

RESUMO

The study was aimed at describing the mode of action of an innovative drug-like congener of fused azaisocytosine-EIMTC (ethyl 8-(4-methoxyphenyl)-4-oxo-6,7-dihydroimidazo[2,1-c][1,2,4]triazine-3-carboxylate)-on cancer cells in early in vitro oncology-related bioassays. Micromolar concentrations of EIMTC were effective at inhibiting the growth of two types of malignant multiple myeloma cells (including cells resistant to thalidomide) while having less cytotoxic effect on normal HSF cells. Furthermore, EIMTC was disclosed as capable of producing the statistically significant decrease in the number of cells in the S phase (in HeLa, TOV112D, T47D and Vero cells) and in the G2/M phase (in TOV112D cells) as well as evoking the distinctly higher necrosis rates in malignant than normal cells of the same epithelial origin. These results are promising in the sense that the bicyclic nucleobase-like structure related to azaisocytosine may target epithelial cancer cells and inhibit their growth while having less effect on normal cells. This may be due to induction of necrosis.


Assuntos
Divisão Celular/efeitos dos fármacos , Citosina/análogos & derivados , Fase G2/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Citosina/farmacologia , Células HeLa , Humanos , Mieloma Múltiplo/patologia
13.
Bioorg Med Chem ; 23(13): 3448-56, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25975637

RESUMO

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.


Assuntos
Antineoplásicos/síntese química , Imidazóis/síntese química , Tiofenos/síntese química , Triazinas/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Pemetrexede/farmacologia , Relação Estrutura-Atividade , Tiofenos/farmacologia , Triazinas/farmacologia
14.
Eur J Pharm Sci ; 68: 114-26, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25528370

RESUMO

The chromatographic behaviour and significant lipophilicity/hydrophobicity indices (log k(w), S, φ(0)) are presented for 21 biologically active fused 1,2,4-triazinones based on the linear relationship: log k = log k(w)-Sφ established for the retention on LC-18 HPLC column, using as mobile phases mixtures of three organic modifiers with water. The effect of these mobile phase modifiers on the chromatographic behaviour of solutes was established and the organic modifier of choice is suggested. The complex correlation of slopes versus intercepts obtained for acetonitrile, contrary to linear ones obtained for methanol and dioxane are disclosed. The observed difference in retention mechanism for acetonitrile compared to methanol and dioxane is explained by intermolecular interactions encoded in lipophilicity. Linear correlations with statistically significant levels between log kw values determined from three different chromatographic systems were obtained. The relationships between log k(w) constants (derived from the linear model for methanol-water mobile phases) and predicted log P and log S values by the use of various computational methods were investigated and these were established with high correlation coefficients. The predicted log P values plotted against φ(0 (MeOH)) indices showed the best fit. Principal component analysis was used to compare various lipophilicity parameters of the solutes and their in silico biological descriptors relevant to optimal pharmacokinetics profile. The similarities and dissimilarities between all the variables and molecular structures of solutes are presented. Statistically significant correlations were found between the chromatographic lipophilicity indices and the calculated pharmacokinetic descriptors: fraction unbound in brain (f(u, brain)), oral bioavailability (%F), permeability and intestinal absorption in jejunum (Caco-2), skin permeation (log K(p)) and blood/brain concentration (log BB).


Assuntos
Modelos Biológicos , Triazinas/química , Triazinas/farmacocinética , 1-Octanol/química , Disponibilidade Biológica , Encéfalo/metabolismo , Simulação por Computador , Humanos , Interações Hidrofóbicas e Hidrofílicas , Absorção Intestinal , Metanol/química , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Absorção Cutânea , Solubilidade , Triazinas/sangue , Água/química
15.
J Chromatogr A ; 1318: 92-101, 2013 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-24157086

RESUMO

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 Abraham's 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.


Assuntos
Analgésicos/isolamento & purificação , Colesterol/química , Cromatografia de Fase Reversa/métodos , Inibidores do Crescimento/isolamento & purificação , Analgésicos/síntese química , Analgésicos/química , Cromatografia de Fase Reversa/instrumentação , Simulação por Computador , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/química , Estrutura Molecular
16.
Bioorg Med Chem ; 21(23): 7465-80, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24126095

RESUMO

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.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Succinatos/química , Succinatos/farmacologia , Triazinas/química , Triazinas/farmacologia , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Succinatos/síntese química , Triazinas/síntese química
17.
Bioorg Med Chem ; 21(13): 3648-66, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23673213

RESUMO

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.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Bases de Schiff/química , Bases de Schiff/farmacologia , Animais , Compostos Azo/química , Compostos Azo/farmacologia , Descoberta de Drogas , Humanos , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
18.
J Cardiothorac Vasc Anesth ; 26(3): 395-402, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22206712

RESUMO

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.


Assuntos
Anestésicos Inalatórios/uso terapêutico , Lesões Encefálicas/prevenção & controle , Ponte de Artéria Coronária/efeitos adversos , Magnésio/sangue , Fármacos Neuroprotetores/uso terapêutico , Idoso , Biomarcadores/sangue , Encéfalo/metabolismo , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/etiologia , Feminino , Proteína Glial Fibrilar Ácida/sangue , Humanos , Isoflurano/uso terapêutico , Masculino , Metaloproteinase 9 da Matriz/sangue , Éteres Metílicos/uso terapêutico , Pessoa de Meia-Idade , Sevoflurano
19.
Chem Biol Interact ; 195(1): 18-24, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22063920

RESUMO

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-ß, 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-ß, 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.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Antioxidantes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hidrazinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Actinas/metabolismo , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular , Citocinas/metabolismo , Etanol , Hidrazinas/síntese química , Hidrazinas/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pirimidinas/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triazóis/farmacologia
20.
Bioorg Med Chem ; 19(17): 5103-16, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21839643

RESUMO

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-Soczewinski 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.


Assuntos
Antineoplásicos/síntese química , Fibroblastos/efeitos dos fármacos , Imidazóis/química , Triazinas/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Cromatografia de Fase Reversa , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Conformação Molecular , Triazinas/síntese química , Triazinas/toxicidade
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