RESUMO
The infections caused by the HSV-1 virus induce lesions on the lips, mouth, face, and eye. In this study, an ethosome gel loaded with dimethyl fumarate was investigated as a possible approach to treat HSV-1 infections. A formulative study was conducted, evaluating the effect of drug concentration on size distribution and dimensional stability of ethosomes by photon correlation spectroscopy. Ethosome morphology was investigated by cryogenic transmission electron microscopy, while the interaction between dimethyl fumarate and vesicles, and the drug entrapment capacity were respectively evaluated by FTIR and HPLC. To favor the topical application of ethosomes on mucosa and skin, different semisolid forms, based on xanthan gum or poloxamer 407, were designed and compared for spreadability and leakage. Dimethyl fumarate release and diffusion kinetics were evaluated in vitro by Franz cells. The antiviral activity against HSV-1 was tested by plaque reduction assay in Vero and HRPE monolayer cells, while skin irritation effect was evaluated by patch test on 20 healthy volunteers. The lower drug concentration was selected, resulting in smaller and longer stable vesicles, mainly characterized by a multilamellar organization. Dimethyl fumarate entrapment in ethosome was 91% w/w, suggesting an almost total recovery of the drug in the lipid phase. Xanthan gum 0.5%, selected to thicken the ethosome dispersion, allowed to control drug release and diffusion. The antiviral effect of dimethyl fumarate loaded in ethosome gel was demonstrated by a reduction in viral growth both 1 h and 4 h post-infection. Moreover, the patch test demonstrated the safety of the ethosomal gel applied on the skin.
Assuntos
Herpesvirus Humano 1 , Absorção Cutânea , Humanos , Fumarato de Dimetilo/farmacologia , Pele/metabolismo , Administração Tópica , Antivirais/farmacologia , Administração Cutânea , Lipossomos/químicaRESUMO
Every year, thousands of tons of fruit seeds are discarded as agro-industrial by-products around the world. Fruit seeds are an excellent source of oils, monounsaturated fatty acids, and n-6 and n-3 polyunsaturated essential fatty acids. This study aimed to develop a novel technology for extracting active substances from selected seeds that were obtained after pressing fruit juices. The proposed technology involved sonification with the use of ethyl alcohol at a low extraction temperature. Seeds of four species-blueberry (Vaccinium myrtillus L.), raspberry (Rubus idaeus), cranberry (Vaccinium macrocarpon), and cuckooflower (Cardamine pratensis)-were used for extraction. Following alcohol evaporation under nitrogen, the antioxidant activity, chemical composition, and volatile compounds of the obtained extracts were analyzed using chromatographic methods, including gas chromatography (GC)-mass spectrometry (MS) (GC-MS/MS), and high-performance liquid chromatography-MS. We analyzed physicochemical properties, fatty acid, and volatile compounds composition, sterol and tocochromanol content of blueberry, cranberry, raspberry, and cuckooflower seed oils obtained by sonication. This method is safe and effective, and allows for obtaining valuable oils from the seeds.
Assuntos
Mirtilos Azuis (Planta)/química , Cardamine/química , Ácidos Graxos/química , Micro-Ondas , Rubus/química , Sementes/química , Vaccinium macrocarpon/química , Compostos Orgânicos Voláteis/química , Cromatografia Gasosa-Espectrometria de MassasRESUMO
AIM OF THE STUDY: To evaluate the inhibitory effect of 17 new analogues of FPh on the Pgp transport function, by estimation of the rhodamine 123 (Rod-123) accumulation inside cultured lymphocytes. MATERIAL AND METHODS: Lymphocyte were cultured in the presence of a lectin (PHA; 2%, v/v), incubated with benzo[α]pyrene (B[α]P; 7.5 µM, 48 h) to induce genotoxic damage and to increase Pgp expression in the cells. Lymphocytes cultured without the tested compounds were considered as controls. RESULTS: It was established that 10 analogues of FPh, among 17 tested, significantly increased Rod-123 accumulation in lymphocytes at the concentration of 10 µM. As compared to the control cultures the Pgp transport function was the most strongly inhibited by 1a, 1b, 1d, 3f, 3h and 3i analogues (approximately by 25%). CONCLUSIONS: FPh analogues 1a, 1b, 1d, 3f, 3h and 3i should be further studied as promising candidates for adjuvant cancer chemotherapeutics.
RESUMO
Two difluoroboron dipyrromethene (BODIPY) based fluorescent dyes - 4,4-difluoro-3-{2-[4-(dimethylamino)phenyl]ethenyl}-8-[4-(methoxycarbonyl)phenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (1) and 4,4-difluoro-3-[2-(4-fluoro-3-hydroxyphenyl)ethenyl]-8-[4-(methoxycarbonyl)phenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (3) - have been synthesized via condensation of p-N,N-dimethylaminobenzaldehyde and 4-fluoro-3-hydroxybenzaldehyde, respectively, with 4,4-difluoro-8-[4-(methoxycarbonyl)phenyl]-1,3,5,7-tetramethyl-3a,4a-diaza-4-bora-s-indacene (2). UV-vis spectrophotometry and steady-state and time-resolved fluorometry have been used to study the spectroscopic and photophysical characteristics of in various solvents. The multi-parameter Kamlet-Taft {pi*, alpha, beta} solvent scales and a new, generalized treatment of the solvent effect, proposed by Catalán (J. Phys. Chem. B, 2009, 113, 5951-5960), have been used in the analysis of the solvatochromic shifts of the UV-vis absorption and fluorescence emission maxima of 1-3, and the rate constants of excited-state deactivation via fluorescence (k(f)) and radiationless decay (k(nr)). The four Catalán solvent scales (dipolarity, polarizability, acidity and basicity of the medium) are the most appropriate for describing the solvatochromic effects. Solvent dipolarity and polarizability are the important causes for the solvatochromism of 1. Conversely, the absorption and emission maxima of 2 and 3 are hardly dependent on the solvent: the small changes reflect primarily the polarizability of the solvent surrounding the dye. Fluorescence decay profiles of 1 can be described by a single-exponential function in aprotic solvents, whereas two decay times are found in alcohols. The fluorescence decays of 2 (lifetimes tau in 1.9-2.9 ns range) and 3 (tau between 3.5 and 4.0 ns) are mono-exponential in all solvents studied. The fluorescence properties of dye are very sensitive to the solvent: upon increasing solvent dipolarity, the fluorescence quantum yields and k(f) values decrease and the emission maxima become more red-shifted. The k(f) values of 2 [(1.6 +/- 0.3) x 10(8) s(-1)] and 3 [(1.5 +/- 0.2) x 10(8) s(-1)] are practically independent of the solvent properties. The crystal structure of reveals that the BODIPY core is nearly planar with the boron atom moved out of the plane. The angle between the phenyl group at the meso-position and the BODIPY plane equals 80 degrees.
RESUMO
Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular mechanism of the biological actions of these molecules is not yet understood in detail. The role of the interactions between phenothiazines and proteins or lipid membranes has been much discussed. Herein, fourier-transform infrared (FTIR) spectroscopic studies were used to investigate the effect of three phenothiazines: fluphenazine (FPh); chlorpromazine (ChP); and propionylpromazine (PP) on the structures of a positively charged poly-l-lysine (PLL) peptide, a negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membrane, and on the mutual interactions between electrostatically associated PLL molecules and DPPC/DPPG membranes. Phenothiazine-induced alterations in the secondary structure of PLL, the conformational state (trans/gauche) of the hydrocarbon lipid chains, and the hydration of the DPPC/DPPG membrane interface were studied on the basis of amide I' vibrations, antisymmetric and symmetric stretching vibrations of the CH2 groups of the lipid hydrocarbon chains (νsCH2), and stretching vibrations of the lipid C=O groups (νCâ¯=â¯O), respectively. It was shown that in the presence of negatively charged DPPC/DPPG membranes, the phenothiazines were able to modify the secondary structure of charged PLL molecules. Additionally, the effect of PLL on the structure of DPPC/DPPG membranes was also altered by the presence of the phenothiazine molecules.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Flufenazina/farmacologia , Fosfatidilgliceróis/metabolismo , Promazina/análogos & derivados , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Polilisina/metabolismo , Promazina/farmacologia , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or ß-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of ß-sheet-rich fibrils from α-helix-rich fibrils of PLL.
Assuntos
Amiloide/metabolismo , Antipsicóticos/efeitos adversos , Doença de Parkinson Secundária/etiologia , Fenotiazinas/efeitos adversos , Polilisina/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Estrutura Secundária de Proteína/efeitos dos fármacos , Amiloide/química , Amiloide/ultraestrutura , Antipsicóticos/química , Dicroísmo Circular , Humanos , Modelos Moleculares , Doença de Parkinson Secundária/metabolismo , Fenotiazinas/química , Polilisina/química , Agregação Patológica de Proteínas/metabolismo , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Resveratrol (Res) is an effective inhibitor of amyloid fibril formation and reduces neuron cell toxicity. The effect of Res on the fibrillogenesis of a polar polypeptide, polyllysine (PLL), was studied by Fourier-transform infrared spectroscopy, vibrational circular dichroism and transmission electron microscopy. Res molecules exhibited strong and specific inhibition of ß-sheet-rich fibrils formed by PLL. Side chain-side chain hydrophobic interactions of Lys side chains in aggregated ß-sheet structures of PLL stabilize this aggregated state, and this interaction is targeted by Res via hydrophobic interactions. The effect of Res on PLL and other previously reported proteins/peptides sequences with fewer polar amino acids reveals that Res shows rather low sequence specificity. Instead, Res targets sequences that support strong hydrophobic interactions. The fibril-inhibition activity of Res, which is specific toward ß-sheet-rich fibrils of proteins/peptides and rather non-specific to the amino acid sequence, indicates that Res is a very promising drug candidate for effective treatment of amyloid-related diseases.
Assuntos
Peptídeos/química , Polilisina/química , Resveratrol/química , Sequência de Aminoácidos , Aminoácidos/química , Amiloide/química , Interações Hidrofóbicas e Hidrofílicas , Conformação Proteica em Folha betaRESUMO
Resveratrol (Res), a natural polyphenol present in different plants and vegetables, exhibits potential therapeutic activity with cardioprotective, antineurodegenerative, antioxidant, and antitumor action. In this study, the effect of Res on the mutual interactions between positively charged poly-l-lysine (PLL) and negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membranes was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA). The interactions between PLL and DPPC/DPPG membranes were strongly affected by the presence of Res molecules. Depending on the Res concentration and method of its supply (through the water or lipid phase) to the studied peptide-membrane systems, the membrane-induced transition of PLL from an α-helix to an extended left-handed polyproline II helix (PPII) occurred at different temperatures, with different cooperativity, or was even completely suppressed. The influence of PLL on the conformational (trans/gauche) state of the hydrocarbon chain region of the lipid membranes and the hydration state of the polar/apolar membrane interface was also modulated by Res, depending on the membrane phase state.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Lipossomos/química , Fosfatidilgliceróis/química , Polilisina/química , Resveratrol/química , Peptídeos/química , Análise de Componente Principal , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier , TemperaturaRESUMO
The effect of halothane, enflurane, sevoflurane, and isoflurane molecules, as volatile anesthetics, on the α-helices and polyproline II extended helices (PPII) of long-chain poly-l-lysine (PLL) were studied using Fourier-transform infrared and vibrational circular dichroism spectroscopy. Uncharged and charged α-helices, as well as charged extended PPII helices, were subjected to anesthetic actions in solvents with different pD values or methanol to water ratios. A crucial factor responsible for hindering the anesthetic-PLL interactions is shown to be the ionization of amino groups of the PLL side chains. The α-helix to ß-sheet transition was triggered only for the uncharged α-helical structures of PLL by the nonpolar anesthetics under study.
Assuntos
Anestésicos/farmacologia , Peptídeos/química , Polilisina/química , Amidas/química , Dicroísmo Circular , Conformação Proteica em alfa-Hélice , Espectroscopia de Infravermelho com Transformada de Fourier , VibraçãoRESUMO
It has been shown that Prodan emission-excitation fluorescence spectroscopy supported by Parallel Factor (PARAFAC) analysis is a fast, simple and sensitive method used in the study of the phase transition from the noninterdigitated gel (Lß') state to the interdigitated gel (LßI) phase, triggered by ethanol and 2,2,2-trifluoroethanol (TFE) molecules in dipalmitoylphosphatidylcholines (DPPC) membranes. The relative contribution of lipid phases with spectral characteristics of each pure phase component has been presented as a function of an increase in alcohol concentration. It has been stated that both alcohol molecules can induce a formation of the LßI phase, but TFE is over six times stronger inducer of the interdigitated phase in DPPC membranes than ethanol molecules. Moreover, in the TFE-mixed DPPC membranes, the transition from the Lß' to LßI phase is accompanied by a formation of the fluid phase, which most probably serves as a boundary phase between the Lß' and LßI regions. Contrary to the three phase-state model of TFE-mixed DPPC membranes, in ethanol-mixed DPPC membranes only the two phase-state model has been detected.
RESUMO
MSAR (1-sulfate-3-myristoyl-5-pentadecylbenzene) is a semisynthetic derivative of 5-n-pentadecylresorcinol (C15:0). MSAR exhibits hemolytic activity against sheep erythrocytes with a EH50 value of (35 +/- 1.7) microM. At low concentrations MSAR also exhibits the ability to protect cells against their hypoosmotic lysis. This protective effect is significant as, at 0.1 microM of MSAR, the extent of osmotically induced cell lysis is reduced by approx. 20%. It was demonstrated that the 9-anthroyloxystearic acid signal was most intensively quenched by MSAR molecules, suggesting a relatively deep location of these molecules within the lipid bilayer. MSAR causes an increase of the fluorescence of the membrane potential sensitive probe. This indicates an alteration of the surface charge and a decrease of the local pH value at the membrane surface. At low bilayer content (1-4 mol%) this compound causes a significant increase of the phospholipid bilayer fluidity (both under and above the main phase transition temperature) of dipalmitoylphosphatidylcholine (DPPC) liposomes. At this low content MSAR slightly decreases the main phase transition temperature (T(c)) value. The effects induced in the phospholipid bilayer by higher contents of MSAR molecules (5-10 mol%) make it impossible to determine the T(c) value and to evaluate changes of the membrane fluidity by using pyrene-labeled lipid. MSAR also causes a decrease of the activity of membrane-bound enzymes - red blood cell acetylcholinesterase (AChE) and phospholipase A2 (PLA2). MSAR decreases the AChE activity by 40% at 100 microM. The presence of MSAR in the liposomal membrane induces a complete abolishment of the lag time of the PLA2 activity, indicating that these molecules induce the formation of packing defects in the bilayer which may result from imperfect mixing of phospholipids.
Assuntos
Membrana Celular/fisiologia , Hemólise/efeitos dos fármacos , Miristatos/síntese química , Miristatos/farmacologia , Resorcinóis/farmacologia , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/fisiologia , Corantes Fluorescentes , Cinética , Bicamadas Lipídicas , Lipídeos/química , Lipídeos/fisiologia , Lipossomos , Fluidez de Membrana/efeitos dos fármacos , Resorcinóis/síntese química , OvinosRESUMO
The temperature-induced α-helix to ß-sheet transition in long-chain poly-l-lysine (PLL), accompanied by the gauche-to-trans isomerization of CH2 groups in the hydrocarbon side chains of Lys amino acid residues, and formation of ß-sheet as well as α-helix fibrillar aggregates of PLL have been studied using Fourier-transform infrared (FT-IR) and vibrational circular dichroism (VCD) spectroscopy, and transmission electron microscopy (TEM). In a low-temperature alkaline water solution or in a methanol-rich water mixture, the secondary structure of PLL is represented by α-helical conformations with unordered and gauche-rich hydrocarbon side chains. Under these conditions, PLL molecules aggregate into α-helical fibrils. PLLs dominated by extended antiparallel ß-sheet structures with highly ordered trans-rich hydrocarbon side chains are formed in a high-temperature range at alkaline pD and aggregate into fibrillar, protofibrillar, and spherical forms. Presented data support the idea that fibrillar aggregation is a varied phenomenon possible in repetitive structural elements with not only a ß-sheet-rich conformation, but also an α-helical-rich conformation.
Assuntos
Polilisina/química , Dicroísmo Circular , Humanos , Microscopia Eletrônica de Transmissão , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier , TemperaturaRESUMO
Fourier-transform infrared, vibrational circular dichroism spectroscopy and transmission electron microscopy are used to follow the structural changes of pure and fluphenazine (FPh)-mixed poly-l-lysine (PLL) triggered by variations of the methanol to water ratio in solvent mixtures. FPh molecules are used as an effective psychotic drug but with a strong Parkinson's-related side effect. To answer the question whether FPh molecules can modify the fibril development, the PLL polypeptide was used as a model of α-helix- and PPII-rich fibrils. It was stated that the presence of FPh molecules did not inhibit the creation of both types of PLL fibrils with clustering features. The methanol-poor aqueous solutions promote the formation of extended polyproline II (PPII) helices; however, the methanol-rich aqueous solutions induce the development of α-helices of both pure and FPh-mixed PLL. Unpredicted and interesting features of PLL fibrillogenesis are evidenced by the formation of uncommon fibrillar aggregates, which are developed in methanol/water solvents from PLL molecules rich in either α-helix or PPII structures. Possibility of PLL molecules to form ß-sheet-, α-helix- and PPII-rich fibrils demonstrating that fibrillogenesis is a common phenomenon, and fibrillar aggregates can be based on all of the basic protein secondary structures.
Assuntos
Flufenazina/farmacologia , Polilisina/química , Solventes/farmacologia , Antipsicóticos/farmacologia , Metanol , Peptídeos/química , Polilisina/efeitos dos fármacos , Multimerização Proteica , Estrutura Secundária de Proteína/efeitos dos fármacos , Solventes/química , ÁguaRESUMO
The effect of inhalation anesthetics (enflurane, isoflurane, sevoflurane or halothane) on the lipid chain-melting phase transition of negatively charged phospholipid membranes was studied using near-infrared (NIR) spectroscopy supported by Principal Component Analysis (PCA). NIR spectra of anesthetics-mixed dipalmitoylphosphatidylglycerol (DPPG) membranes were recorded in a range of the first overtone of the symmetric and antisymmetric stretching vibrations of CH2 groups of lipid aliphatic chains as a function of increasing temperature. Anesthetic-dependent changes in the trans to gauche conformers ratio of CH2 groups in the hydrocarbon lipid chains were characterized in detail and compared with the zwitterionic lipid membranes, which were built of dipalmitoylphosphatidylcholine (DPPC) molecules.
Assuntos
Anestésicos/química , Lipossomos/química , Fosfatidilgliceróis/química , Bicamadas Lipídicas/química , Lipossomos/metabolismo , Transição de Fase , Fosfatidilgliceróis/metabolismo , Análise de Componente Principal , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Long-chain alkylresorcinols (ARs) are commonly found in plant and bacteria cells, and they exhibit a wide variety of biological effects, including antifungal, antitumor, and antiphrastic activities. The cholesterol (Chol)-like effect of ARs with hydrocarbon side-chain lengths ranging from C15 to C25 on the structure of pure and Chol-doped dipalmitoylphosphocholine (DPPC) and sphingomyelin (SM) membranes was investigated by Laurdan fluorescence spectroscopy. The Laurdan emission generalized polarization parameter was analyzed as a function of the temperature and excitation wavelength in DPPC (or SM)/Chol, DPPC (or SM)/AR, and DPPC/Chol/AR systems. It was found that AR incorporation into both DPPC and SM bilayers induces an increase in the temperature of the main lipid phase transition, similar to the effect of Chol molecule incorporation. The phase separation, lipid-chain ordering, and membrane hydration are discussed for the AR-mixed membranes and compared with DPPC (or SM)/Chol membranes.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Bicamadas Lipídicas/química , Transição de Fase/efeitos dos fármacos , Resorcinóis/farmacologia , Esfingomielinas/química , Alquilação , Resorcinóis/química , Espectrometria de Fluorescência/métodos , Relação Estrutura-Atividade , Temperatura de Transição/efeitos dos fármacosRESUMO
Fluphenazine (FPh) belongs to the phenothiazine family of compounds and exhibits a wide variety of biological effects, including antimutagenic, proapoptotic, antiproliferative and anti-multidrug resistance (MDR) activities. The ability of FPh to interact with lipid membranes can have a significant impact on its biological activities. However, the mechanisms involved in the interaction of FPh with lipid membranes are poorly understood. FTIR-ATR spectroscopy has been used in this study to visualize the interactions between FPh and a model lipid bilayer composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Subsequent interpretation of the temperature-dependent FTIR spectra obtained for FPh:DPPC systems containing different concentrations of FPh was efficiently supported by principal component analysis.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , Antagonistas de Dopamina/química , Flufenazina/química , Bicamadas Lipídicas/química , 1,2-Dipalmitoilfosfatidilcolina/química , Modelos Moleculares , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Phenothiazine compounds are known as effective inhibitors of a multidrug resistance (MDR) of tumor cells to chemotherapeutic agents. This group consists of many important substances used in human medicine such as antipsychotic drugs in the case of fluphenazine (FPh) or chlorpromazine (CPZ). Fluphenazine was on the World Health Organization (WHO) list of Essential Medicines of 2009, and its new pyrimidine analog (FPh-prm) presented in this work has been documented to have a high anti-MDR activity. In order to discover the character of alterations of the lipid bilayer structure caused by the presence of FPh-prm inside the lipid membrane, which is responsible for the essential increase of an anti-MDR activity of FPh-prm, microcalorimetric (differential scanning calorimetry), Laurdan fluorescence, (31)P nuclear magnetic resonance spectroscopy (NMR), and attenuated total reflectance Fourier transfer infrared spectroscopy (FTIR-ATR) were used for dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes mixed with a different concentration of amine analogue. It was stated that the formation of domains with different content of FPh-prm/DPPC can be a reason for the membrane-related mechanism of chemoprevention associated with the inhibition of the outward transport of anticancer drugs by the glycoprotein P (Pgp) in cancer cells by the pyrimidine analog of FPh. To our best knowledge, this report is the first to show the bilayer structure of domains formed by incomplete miscibility of fluphenazine-related compounds and phospholipid molecules. Our results provide a sound basis for the design of future modifications of anti-MDR drugs by providing very effective inhibitors of the pump activity of Pgp.
Assuntos
Antineoplásicos/química , Antipsicóticos/química , Flufenazina/química , Bicamadas Lipídicas/química , Fosfatidilcolinas/química , Pirimidinas/química , 1,2-Dipalmitoilfosfatidilcolina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Varredura Diferencial de Calorimetria , Resistência a Múltiplos Medicamentos , Flufenazina/síntese química , Humanos , Lipossomos/química , Espectroscopia de Ressonância Magnética , Fósforo/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The long chain Mannich bases, especially with the piperidine and morpholine groups, display very promising antimicrobial activity. In order to extend our knowledge on their impact on biological systems, we examined the interactions of the 5-pentadecyl-2-((piperidin-1-yl)methyl)phenol (PPDP) with model lipid membrane by means of differential scanning calorimetry (DSC) and fluorescence measurements. The small unilamellar vesicles of dipalmitoylophosphatidylcholine (DPPC) with different piperidine Mannich base concentration were investigated as a function of the increase of temperature. The phase separation accompanied by the rise of the transition enthalpy of both subcomponents, the increase of the function of the GP values of Laurdan versus the wavelength of excitation in the gel phase of PPDP/DPPC systems, and no remarkable differences in the fluorescence anisotropy of PPDP molecules in lipid environment for different mixtures of PPDP/DPPC was observed. Additionally, it was shown that PPDP itself interdigitated in solid state.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Lipossomos/metabolismo , Bases de Mannich/metabolismo , Piperidinas/metabolismo , Varredura Diferencial de Calorimetria , Bases de Mannich/química , Transição de Fase , Piperidinas/química , Espectrometria de FluorescênciaRESUMO
Phenothiazines belong to the oldest, synthetic antipsychotic drugs, which do not have their precursor in the world of natural compounds. Apart from their fundamental neuroleptic action connected with the dopaminergic receptors blockade, phenothiazine derivatives also exert diverse biological activities, which account for their cancer chemopreventive-effect, as: calmodulin- and protein kinase C inhibitory-actions, anti-proliferative effect, inhibition of P-glycoprotein transport function and reversion of multidrug resistance. According to literature data on relations between chemical structure of phenothiazines and their biological effects, the main directions for further chemical modifications have been established. They are provided and discussed in this review paper.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Fenotiazinas/química , Fenotiazinas/farmacologia , Quimioprevenção , Resistência a Múltiplos Medicamentos , Relação Estrutura-AtividadeRESUMO
The influence of 3-pentadecylphenol (PDP) on the structure and physicochemical properties of the lipid bilayers of DPPC liposomes was studied using ATR-IR and (31)P NMR methods. On the basis of analysis of the bands assigned to the CH(2) stretching, CH(2) scissoring, C=O stretching, and PO(2)(-) stretching vibrations it was revealed that PDP influences both the hydrophobic and hydrophilic parts of the DPPC liposome bilayer. Analysis of the (31)P NMR line-shape indicated a lamellar to non-lamellar phase transition in PDP-doped DPPC dispersions. It was shown that PDP/DPPC isotropic aggregates have similar nuC=O and nu(as)PO(2)(-) band positions and lower gauche populations in the hydrophobic chain region compared with the DPPC bilayer in the liquid-crystal phase.