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1.
Molecules ; 26(17)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34500676

RESUMO

Phenothiazines are known as synthetic antipsychotic drugs that exhibit a wide range of biological effects. Their properties result from the structure and variability of substituents in the heterocyclic system. It is known that different quantum chemical properties have a significant impact on drug behavior in the biological systems. Thus, due to the diversity in the chemical structure of phenothiazines as well as other drugs containing heterocyclic systems, quantum chemical calculations provide valuable methods in predicting their activity. In our study, DFT computations were applied to show some thermochemical parameters (bond dissociation enthalpy-BDE, ionization potential-IP, proton dissociation enthalpy-PDE, proton affinity-PA, and electrontransfer enthalpy-ETE) describing the process of releasing the hydrogen/proton from the hydroxyl group in the side chain of four 2-(trifluoromethyl)phenothiazine (TFMP) derivatives and fluphenazine (FLU). Additional theoretical analysis was carried out based on QTAIM theory. The results allowed theoretical determination of the ability of compounds to scavenge free radicals. In addition, the intramolecular hydrogen bond (H-bond) between the H-atom of the hydroxyl group and the N-atom located in the side chain of the investigated compounds has been identified and characterized.

2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445104

RESUMO

Phenolic acids possess many beneficial biological activities, including antioxidant and anti-inflammatory properties. Unfortunately, their low bioavailability restricts their potential medical uses, as it limits the concentration of phenolic acids achievable in the organism. The conjugation with phospholipids constitutes one of the most effective strategies to enhance compounds bioavailability in biological systems. In the present study, the conjugates of anisic (ANISA) and veratric acid (VA) with phosphatidylcholine (PC) were investigated. Since both ANISA and VA are inhibitors of tyrosinase, a melanocyte enzyme, the expression of which increases during tumorigenesis, anticancer potential of the conjugates was tested in several metastatic melanoma cell lines. The conjugates proved to be antiproliferative, apoptosis-inducing and cell-cycle-affecting agents, selective for cancerous cells and not affecting normal fibroblasts. The conjugates substituted by ANISA and VA, respectively, at both the sn-1 and sn-2 positions of PC, appeared the most promising, since they were effective against the vast majority of metastatic melanoma cell lines. Additionally, the conjugation of phenolic acids to PC increased their antioxidant activity. Molecular modeling was employed for the first time to estimate the features of the investigated conjugates relevant to their anticancer properties and membrane permeation. Again, the conjugates substituted by phenolic acid at both the sn-1 and sn-2 positions of PC seemed to be presumably most bioavailable.


Assuntos
Antineoplásicos/farmacologia , Hidroxibenzoatos/farmacologia , Melanoma/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Fosfolipídeos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Fibroblastos/efeitos dos fármacos , Humanos , Fosfatidilcolinas/farmacologia , Ácido Vanílico/análogos & derivados , Ácido Vanílico/farmacologia
3.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33065997

RESUMO

Terpenes constitute one of the largest groups of natural products. They exhibit a wide range of biological activities including antioxidant, anticancer, and drug resistance modulating properties. Saffron extract and its terpene constituents have been demonstrated to be cytotoxic against various types of cancer cells, including breast, liver, lung, pancreatic, and colorectal cancer. In the present work, we have studied anticancer properties of TMPE, a newly synthesized monoterpene derivative of ß-cyclocitral-the main volatile produced by the stigmas of unripe crocuses. TMPE presented selective cytotoxic activity to doxorubicin-resistant colon cancer cells and was identified to be an effective MDR modulator in doxorubicin-resistant cancer cells. Synergy between this derivative and doxorubicin was observed. Most probably, TMPE inhibited transport activity of ABCB1 protein without affecting its expression level. Analysis of TMPE physicochemical parameters suggested it was not likely to be transported by ABCB1. Molecular modeling showed TMPE being more reactive molecule than the parental compound-ß-cyclocitral. Analysis of electrostatic potential maps of both compounds prompted us to hypothesize that reduced reactivity as well as susceptibility to electrophilic attack were related to the lower general toxicity of ß-cyclocitral. All of the above pointed to TMPE as an interesting candidate molecule for MDR reversal in cancer cells.


Assuntos
Antineoplásicos , Neoplasias do Colo/metabolismo , Crocus/química , Cicloexenos/química , Resistencia a Medicamentos Antineoplásicos , Compostos Orgânicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aldeídos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Cicloexenos/farmacologia , Diterpenos/química , Células HT29 , Humanos , Compostos Orgânicos/síntese química , Compostos Orgânicos/farmacologia , Ligação Proteica
4.
Eur J Pharmacol ; 849: 124-134, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30721703

RESUMO

The idea of the use of anticancer drugs together with a chemosensitizer emerged as the strategy of reversal of multidrug resistance (MDR) of cancer cells expressing ABC proteins many years ago. The approaches relying on the use of a single chemosensitizer have never resulted in a clinical success. Therefore, the application of drug combinations of two or more compounds with different mechanisms of action might be an alternative approach to increase the success rate. In the present study the cytotoxic and NF-κB inhibition potential of the phenothiazine derivative, MAE-TPR, was evaluated. MAE-TPR was demonstrated to be an effective doxorubicin-resistance modulator in human adenocarcinoma cell line LoVo/Dx. In the presence of MAE-TPR cytotoxicity of doxorubicin was elevated, and its intracellular accumulation increased. Strong synergism occurred between MAE-TPR and Dox. MAE-TPR diminished also the expression of ABCB1 transporter (P-glycoprotein) by affecting NF-κB pathway. Theobromine, a phytochemical from cocoa, which was barely active itself, strongly augmented MDR reversal potency of MAE-TPR. The effect of the combination of phenothiazine derivative with theobromine on cancer cells was studied for the first time in the present work. It was concluded that the use of the proposed combination of two modulators might be a promising strategy for MDR reversal since modulators could be used in concentrations much lower than in case of their single application and in that way the risk of intolerable side-effects could be reduced.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cacau/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Fenotiazinas/química , Fenotiazinas/farmacologia , Teobromina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , NF-kappa B/metabolismo , Teobromina/química
5.
Biomed Pharmacother ; 106: 624-636, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29990852

RESUMO

Cancer cells often develop the resistance to pro-apoptotic signaling that makes them invulnerable to conventional treatment. Therapeutic strategies that make cancer cells enter the path of apoptosis are desirable due to the avoidance of inflammatory reaction that usually accompanies necrosis. In the present study phenothiazines (fluphenazine and four recently synthesized derivatives) were investigated in order to identify compounds with a potent anticancer activity. Since phenothiazines are known as multidrug resistance modulators the sensitive human colorectal adenocarcinoma cell line (LoVo) and its doxorubicin-resistant, ABCB1 overexpressing, subline (LoVo/Dx) have been employed as a model system. In studied cancer cells cytotoxic effect of the phenothiazine derivatives was accompanied by apoptosis and autophagy induction as well as by the increase of cellular lipid peroxidation and intracellular reactive oxygen species generation. Molecular modelling revealed that reactivity of phenothazines (manifested by their low energy gap) but not lipophilicity was positively correlated with their anticancer potency, pro-oxidant properties and apoptosis induction ability. Additionally, some of the studied compounds turned out to be more potent cytotoxic and pro-apoptotic agents in doxorubicin-resistant (LoVo/Dx) cells than in sensitive ones (LoVo). The hypothesis was assumed that studied phenothiazine derivatives induced apoptotic cell death by increasing the production of reactive oxygen species.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Peroxidação de Lipídeos/efeitos dos fármacos , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Flufenazina/síntese química , Flufenazina/farmacologia , Humanos , Modelos Moleculares , Estresse Oxidativo/efeitos dos fármacos , Fenotiazinas/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
6.
Acta Pol Pharm ; 71(6): 1004-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25856831

RESUMO

The purpose of the present paper was to assess the ability of new piroxicam analogues to interact with the lipid bilayers. The results of calorimetric and fluorescence spectroscopic experiments of two new synthesized analogues of piroxicam, named PR17 and PR18 on the phase behavior of phospholipid bilayers and fluorescence quenching of fluorescent probes (Laurdan and Prodan), which molecular location within membranes is known with certainty, are shown in present work. The presented results revealed that, depending on the details of chemical structure, the studied compounds penetrated the lipid bilayers.


Assuntos
Anti-Inflamatórios não Esteroides/química , Bicamadas Lipídicas/química , Fosfatidilcolinas/química , Piroxicam/análogos & derivados , Piroxicam/química , 1,2-Dipalmitoilfosfatidilcolina/química , Anti-Inflamatórios não Esteroides/farmacologia , Calorimetria , Gema de Ovo/química , Modelos Moleculares , Estrutura Molecular , Piroxicam/farmacologia , Relação Quantitativa Estrutura-Atividade , Espectrometria de Fluorescência , Termografia
7.
Acta Pol Pharm ; 71(6): 1045-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25745777

RESUMO

A novel series of potentially biologically active 1,2-benzothiazine 1,1-dioxides--analogs of piroxicam (a recognized non-steroidal anti-inflammatory drug) were synthesized from commercially available saccharin. All of the synthesized compounds were subjected to preliminary evaluation for their ability to interact with lipid bilayers. The influence of the new derivatives of piroxicam on liposomes made of EYPC was investigated by fluorescence spectroscopy with two fluorescent probes--Laurdan and Prodan. All the studied compounds showed an interaction with model membranes.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Bicamadas Lipídicas/química , Piroxicam/análogos & derivados , Piroxicam/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Moleculares , Estrutura Molecular , Piroxicam/química , Piroxicam/farmacologia , Espectrometria de Fluorescência
8.
Anticancer Res ; 33(3): 857-63, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23482754

RESUMO

AIM: This study aimed to evaluate the influence of phenothiazine derivatives (PDs) on the intracellular accumulation of cyanine dye DiOC6(3) in doxorubicin-resistant LoVo-DX cell line, with overexpression of P-glycoprotein. MATERIALS AND METHODS: In order to maintain a high expression level of P-gp, the LoVo-DX cells were grown in the presence of doxorubicin (100 ng/ml). The time-dependent fluorescence signal (T-DFS) of the intracellular accumulation of DiOC6(3), in the presence of PDs, was then recorded. The rate constants k1, k2, k3 and amplitudes of T-DFS, describing the intracellular accumulation process, were determined based on the respective theoretical equation. RESULTS: The values of k1 and k2 were dependent on the hydrophobicity (logP) of the PDs used as drug resistance modulators. A rise of k1 and k2 values was observed when the logP of PDs increased. CONCLUSION: We suggest that the k1 and k2 rate constants could be regarded as useful parameters for assessment of PDs as well as of other compounds of potential application as reversers of multidrug resistance.


Assuntos
Carbocianinas/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/farmacologia , Corantes Fluorescentes/farmacocinética , Fenotiazinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos Antineoplásicos , Microscopia Confocal , Espectrometria de Fluorescência , Células Tumorais Cultivadas
9.
Exp Biol Med (Maywood) ; 235(1): 98-110, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20404024

RESUMO

In photodynamic therapy (PDT) a tumor-selective photosensitizer is administered and then activated by exposure to a light source of appropriate wavelength. Multidrug resistance (MDR) is largely caused by the drug efflux from the tumor cell by means of P-glycoprotein, resulting in reduced efficacy of the anticancer therapy. This study deals with photodynamic therapy with Photofrin (Ph) on colon cancer cell lines (doxorubicin-sensitive and -resistant). The cells were treated with 15 and 30 microg/mL Ph and then irradiated by a light dose of 3 or 6 J/cm(2) (632.8 nm). After irradiation the cells were incubated for 0, 3 or 18 h. Crucial factors of oxidative stress (thiobarbituric acid reactive substances [TBARS], protein damage, thiazolyl blue tetrazolium bromide [MTT] assay), changes in cytosolic superoxide dismutase (SOD1) activity after photodynamic reaction (PDR), and the intracellular accumulation of photosensitizers in the cells were examined. Moreover, the expressions of glutathione S-transferase (GST)-pi, a marker protein for photochemical toxicity, and secretory phospholipase A(2), a prognostic and diagnostic marker for colon cancers, were determined. After PDR, increases in SOD1 activity and the level of TBARS were observed in both cell lines. The level of protein-associated -SH groups decreased after PDR. Both cell lines demonstrated stronger GST-pi and PLA(2) expression after PDR, especially after 18 h of incubation. The increasing level of reactive oxygen species following the oxidation of sulfhydryl cell groups and lipid peroxidation influence the activity of many transporters and enzymes. The changes in SOD1 activity show that photodynamic action generates oxidative stress in treated cells. Our study presents that PDR caused oxidative alterations in both examined colon adenocarcinoma cell lines. However, the MDR cells reacted more slowly and all oxidative changes occurred in the delay.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Fotorradiação com Hematoporfirina , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Éter de Diematoporfirina/uso terapêutico , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glutationa S-Transferase pi/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo , Fármacos Fotossensibilizantes/uso terapêutico , Proteínas/química , Proteínas/metabolismo , Compostos de Sulfidrila/química , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
10.
Folia Histochem Cytobiol ; 45(2): 93-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17597022

RESUMO

In photodynamic therapy (PDT), a tumor-selective photosensitizer is administered and then activated by exposure to a light source of applicable wavelength. Multidrug resistance (MDR) is largely caused by the efflux of therapeutics from the tumor cell by means of P-glycoprotein (P-gp), resulting in reduced efficacy of the anticancer therapy. This study deals with photodynamic therapy with Photofrin II (Ph II) and hypericin (Hyp) on sensitive and doxorubicin-resistant colon cancer cell lines. Changes in cytosolic superoxide dismutase (SOD1) activity after PDT and the intracellular accumulation of photosensitizers in sensitive and resistant colon cancer cell lines were examined. The photosensitizers' distributions indicate that Ph II could be a potential substrate for P-gp, in contrast to Hyp. We observed an increase in SOD1 activity after PDT for both photosensitizing agents. The changes in SOD1 activity show that photodynamic action generates oxidative stress in the treated cells. P-gp appears to play a role in the intracellular accumulation of Ph II. Therefore the efficacy of PDT on multidrug-resistant cells depends on the affinity of P-gp to the photosensitizer used. The weaker accumulation of photosensitizing agents enhances the antioxidant response, and this could influence the efficacy of PDT.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias do Colo/enzimologia , Citosol/enzimologia , Éter de Diematoporfirina/metabolismo , Perileno/análogos & derivados , Fotoquimioterapia , Superóxido Dismutase/metabolismo , Antracenos , Linhagem Celular Tumoral , Citosol/efeitos dos fármacos , Éter de Diematoporfirina/farmacologia , Humanos , Perileno/metabolismo , Perileno/farmacologia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia
11.
Eur J Pharm Sci ; 21(4): 421-7, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14998572

RESUMO

The partition coefficients (K(p)) between lipid bilayer of phosphatidylcholine (PC) vesicles and buffer for five new phenothiazines were determined using the second derivatives of ultraviolet absorption spectra. The lambda(max) of absorption band for each of the investigated phenothiazine derivatives (PDs) was shifted to the longer wavelengths in the presence of PC vesicles with increasing of lipid concentration. As a result of light scattering in liposome suspension no isosbestic point could be observed in absorption spectra. However, the background signal could be eliminated using the method of second derivative of absorption spectra. In the second derivative of absorption spectra two isosbestic points were observed. Changes of intensity (Delta D) of second derivative of absorption spectra at the lambda(max) (wavelength of absorption maximum for drug in buffer) caused by the increase in lipid concentration were measured for set of phenothiazine derivatives. K(p) for these drugs were calculated from the relationship between Delta D and lipid concentration. The K(p) values for all studied phenothiazine derivatives are in the order of magnitude of 10(5) and they increase about 1.7-fold when length of the alkyl phenothiazine chain was enhanced by addition of the each next one (-CH(2)) group. Substitution of -H atom by -CF(3) group at position 2 of phenothiazine ring results in 3.5-fold increase in K(p) values.


Assuntos
Bicamadas Lipídicas/análise , Lipossomos/análise , Fenotiazinas/análise , Água/análise , Dimetil Sulfóxido/análise , Dimetil Sulfóxido/química , Bicamadas Lipídicas/química , Lipossomos/química , Fenotiazinas/química , Espectrofotometria Ultravioleta/métodos , Água/química
12.
Mol Membr Biol ; 20(1): 53-60, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12745926

RESUMO

Although phenothiazines are known as multidrug resistance modifiers, the molecular mechanism of their activity remains unclear. Since phenothiazine molecules are amphiphilic, the interactions with membrane lipids may be related, at least partially, to their biological effects. Using the set of phenothiazine maleates differing in the type of phenothiazine ring substitution at position 2 and/or in the length of the alkyl bridge-connecting ring system and side chain group, we investigated if their ability to modulate the multidrug resistance of cancer cells correlated with model membrane perturbing potency. The influence exerted on lipid bilayers was determined by liposome/buffer partition coefficient measurements (using the absorption spectra second-derivative method), fluorescence spectroscopy and calorimetry. Biological effects were assessed by a flow cytometric functional test based on differential accumulation of fluorescent probe DiOC(2)(3) by parental and drug-resistant cells. We found that all phenothiazine maleates were incorporated into lipid bilayers and altered their biophysical properties. With only few exceptions, the extent of membrane perturbation induced by phenothiazine maleates correlated with their lipophilicity. Within the group of studied derivatives, the compounds substituted with CF(3)- at position 2 of phenothiazine ring were the most active membrane perturbants. No clear relation was found between effects exerted by phenothiazine maleates on model membranes and their ability to modulate P-glycoprotein transport activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membrana Celular/efeitos dos fármacos , Fenotiazinas/química , Fenotiazinas/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Calorimetria , Carbocianinas/química , Membrana Celular/metabolismo , Citometria de Fluxo/métodos , Corantes Fluorescentes/química , Bicamadas Lipídicas/química , Lipossomos , Linfoma/tratamento farmacológico , Maleatos/química , Camundongos , Fenotiazinas/farmacocinética , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Eur J Pharm Sci ; 16(3): 201-8, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12128175

RESUMO

The mechanisms of some biological effects exerted by flavonoids (e.g. activity against lipid oxidation, multidrug resistance modulation) may involve their interactions with lipid bilayers. Due to variety of substituents attached to the flavonoid nucleus individual isoflavones significantly differ in their properties; in particular they may differently interact with membranes. For this reason we have investigated the interactions of different isoflavones with lipid bilayers. The influence of four plant isoflavones on the phase transitions of dipalmitoylphosphatidylcholine (DPPC) and on liposome aggregation was studied, using microcalorimetry and absorption measurements, respectively. We found that isoflavones substituted with one or two prenyl groups less effectively induce liposome aggregation than more polar ones, possessing no prenyl groups. For aggregation-promoting compounds, rather small differences in the influence on phosphatidylcholine, phosphatidylserine and phosphatidylinositol liposomes were recorded. On the other hand, the alteration of DPPC phase transitions by prenyl-substituted isoflavones was more pronounced than changes induced by non-prenyl ones. On the basis of observed effects we conclude that prenyl-substituted isoflavones penetrate deeper into the lipid bilayer while more polar ones act closer to the membrane surface. Comparing our results with biological tests it seems that interactions with the hydrophobic core of membranes are responsible for the activity of the studied isoflavones.


Assuntos
Isoflavonas/farmacocinética , Bicamadas Lipídicas/metabolismo , Sophora/química , Isoflavonas/química , Isoflavonas/isolamento & purificação , Lipossomos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacocinética
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