RESUMEN
Resveratrol is converted to various metabolites by gut microbiota. Human and rat liver 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) are critical for glucocorticoid activation, while 11ß-HSD2 in the kidney does the opposite reaction. It is still uncertain whether resveratrol and its analogues selectively inhibit 11ß-HSD1. In this study, the inhibitory strength, mode of action, structure-activity relationship (SAR), and docking analysis of resveratrol analogues on human, rat, and mouse 11ß-HSD1 and 11ß-HSD2 were performed. The inhibitory strength of these chemicals on human 11ß-HSD1 was dihydropinosylvin (6.91 µM) > lunularin (45.44 µM) > pinostilbene (46.82 µM) > resveratrol (171.1 µM) > pinosylvin (193.8 µM) > others. The inhibitory strength of inhibiting rat 11ß-HSD1 was pinostilbene (9.67 µM) > lunularin (17.39 µM) > dihydropinosylvin (19.83 µM) > dihydroresveratrol (23.07 µM) > dihydroxystilbene (27.84 µM) > others and dihydropinosylvin (85.09 µM) and pinostilbene (>100 µM) inhibited mouse 11ß-HSD1. All chemicals did not inhibit human, rat, and mouse 11ß-HSD2. It was found that dihydropinosylvin, lunularin, and pinostilbene were competitive inhibitors of human 11ß-HSD1 and that pinostilbene, lunularin, dihydropinosylvin, dihydropinosylvin and dihydroxystilbene were mixed inhibitors of rat 11ß-HSD1. Docking analysis showed that they bind to the steroid-binding site of human and rat 11ß-HSD1. In conclusion, resveratrol and its analogues can selectively inhibit human and rat 11ß-HSD1, and mouse 11ß-HSD1 is insensitive to the inhibition of resveratrol analogues.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Simulación del Acoplamiento Molecular , Resveratrol , Estilbenos , Resveratrol/análogos & derivados , Resveratrol/farmacología , Resveratrol/química , Animales , Humanos , Ratas , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Ratones , Estilbenos/química , Estilbenos/farmacología , Simulación de Dinámica Molecular , Relación Estructura-Actividad , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Relación Estructura-Actividad Cuantitativa , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/químicaRESUMEN
The targeted compounds in this research, resveratrol analogs 1-14, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 µM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.
Asunto(s)
Antioxidantes , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Resveratrol , Resveratrol/análogos & derivados , Resveratrol/química , Resveratrol/farmacología , Resveratrol/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Humanos , Relación Estructura-ActividadRESUMEN
Tapinarof (3,5-dihydroxy-4-isopropylstilbene) is a therapeutic agent used in the treatment of psoriasis (VTAMA®). In this study, we examined the redox behaviour, (photo)stability, (photo)toxicity and (bio)transformation of tapinarof in the context of a structure-activity relationship study. Selected derivatives of the structurally related tapinarof were investigated, namely resveratrol, pterostilbene, pinosylvin and its methyl ether. Tapinarof undergoes electrochemical oxidation in a neutral aqueous medium at a potential of around +0.5 V (vs. Ag|AgCl|3M KCl). The anodic reaction of this substance is a proton-dependent irreversible and adsorption-driven process. The pKa value of tapinarof corresponds to 9.19 or 9.93, based on empirical and QM calculation approach, respectively. The oxidation potentials of tapinarof and its analogues correlate well with their HOMO (highest occupied molecular orbital) energy level. The ability to scavenge the DPPH radical decreased in the order trolox ≥ resveratrol > pterostilbene > tapinarof > pinosylvin â« pinosylvin methyl ether. It was also confirmed that tapinarof, being a moderate electron donor, is able to scavenge the ABTS radical and inhibit lipid peroxidation. The 4'-OH group plays a pivotal role in antioxidant action of stilbenols. During the stability studies, it was shown that tapinarof is subject to spontaneous degradation under aqueous conditions, and its degradation is accelerated at elevated temperatures and after exposure to UVA (315-399 nm) radiation. In aqueous media at pH 7.4, we observed an â¼50 % degradation of tapinarof after 48 h at laboratory temperature. The main UVA photodegradation processes include dihydroxylation and hydration. In conclusion, the phototoxic effect of tapinarof on a human keratinocytes cell line (HaCaT) was evaluated. Tapinarof exhibited a clear phototoxic effect, similar to phototoxic standard chlorpromazine. The IC50 values of the cytotoxicity and phototoxic effects of tapinarof correspond to 27.6 and 3.7 µM, respectively. The main HaCaT biotransformation products of tapinarof are sulfates and glucuronides.
Asunto(s)
Queratinocitos , Oxidación-Reducción , Estilbenos , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Relación Estructura-Actividad , Estilbenos/farmacología , Estilbenos/química , Dermatitis Fototóxica , Resveratrol/farmacología , Resveratrol/análogos & derivados , Resveratrol/química , Rayos Ultravioleta , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Piel/patología , Antioxidantes/farmacología , Antioxidantes/química , Células HaCaTRESUMEN
Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients' outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, including anticancer effects. In this study, we explored the antiproliferative activities of newly synthetized RSV analogues in a panel of PC cell lines and evaluated the physicochemical properties of the most active compound. This derivative exhibited marked antiproliferative effects in PC cells through mechanisms involving DNA damage, apoptosis induction, and interference in cell cycle progression, as assessed using flow cytometry and immunoblot analysis of cell cycle proteins, PARP cleavage, and H2AX phosphorylation. Notably, the compound induced a consistent reduction in the PC cell subpopulation with a CD133+EpCAM+ stem-like phenotype, paralleled by dramatic effects on cell clonogenicity. Moreover, the RSV derivative had negligible toxicity against normal HFF-1 cells and, thus, good selectivity index values toward PC cell lines. Remarkably, its higher lipophilicity and stability in human plasma, as compared to RSV, might ensure a better permeation along the gastrointestinal tract. Our results provide insights into the mechanisms of action contributing to the antiproliferative activity of a synthetic RSV analogue, supporting its potential value in the search for effective and safe agents in PC treatment.
Asunto(s)
Células Madre Neoplásicas , Neoplasias Pancreáticas , Polifenoles , Resveratrol , Humanos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Pancreáticas/patología , Polifenoles/farmacología , Polifenoles/uso terapéutico , Resveratrol/análogos & derivados , Resveratrol/farmacología , Resveratrol/uso terapéutico , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/fisiología , Neoplasias PancreáticasRESUMEN
Thrombin is a potent platelet activator and a key mediator of blood coagulation, thereby playing a crucial role in cardiovascular disease. Recently, protease-activated receptor 4 (PAR4), one of thrombin receptors in human platelets, is emerging as a promising target for antiplatelet therapy. 3,5,2',4'-Tetramethoxystilbene (TMS), a resveratrol analog, have demonstrated promising effects on preventing atherosclerosis and hypertension, whereas its antiplatelet effect has never been investigated. Herein we show that TMS at concentrations of a few micromolar selectively inhibits PAR4-mediated human platelet aggregation, ATP secretion, integrin αIIbß3 activation, and signaling pathways. In a whole-blood model of arterial flow, TMS also significantly reduced in vitro thrombus formation. Analysis of the structure-activity relationships of TMS and a panel of stilbene analogs reveal that full methylation of hydroxy groups of the stilbenes is the critical structural determinant for the anti-PAR4 activity. Our results suggest that fully methylated resveratrol analogs with anti-PAR4 activity are potential candidates for development of novel antiplatelet agents.
Asunto(s)
Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Resveratrol , Trombosis , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Receptores de Trombina/metabolismo , Resveratrol/análogos & derivados , Resveratrol/farmacología , Trombosis/prevención & controlRESUMEN
Acylated derivatives of the dietary phenolic, resveratrol, were prepared via enzymatic and chemical transesterification modification with selected vinyl fatty acids to expand the potential application of resveratrol and its acylated derivatives in functional supplement, cosmetic/skincare, and pharmaceutical fields. The acylation was implemented using eight vinyl fatty acids with varying chain lengths (C2:0-C18:0). Eight monoesters enzymatically prepared, eight diesters and four triesters, chemically prepared, were isolated and purified and identified via MS (mass spectra) or/and NMR (nuclear magnetic resonance). The lipophilicity of resveratrol and its acylated derivatives was calculated using ALOGPS 2.1. Compared with related acylated products, resveratrol itself rendered higher antioxidant efficacy in all the antioxidant assays, namely DPPH, ABTS, FRAP, and ferrous chelation tests. Within various ester derivatives of resveratrol, short-chain fatty acid mono- and di-substituted resveratrols, especially the resveratrol monoacetate/diacetate, exhibited higher antioxidant efficacy in DPPH and ABTS assays than the rest of resveratrol derivatives, but the medium-chain monoesters of resveratrol, including caproate, caprylate, caprate, and laurate, showed a higher metal ion chelation ability compared to other acylated resveratrols. These results imply that resveratrol derivatives may be used in lipidic media as health-beneficial antioxidants.
Asunto(s)
Antioxidantes/química , Resveratrol/análogos & derivados , Acilación , Antioxidantes/farmacología , Compuestos de Bifenilo/química , Esterificación , Radicales Libres/química , Humanos , Picratos/química , Resveratrol/farmacologíaRESUMEN
Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (-)-malibatol A, (-)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (-)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.
Asunto(s)
Productos Biológicos/química , Diseño de Fármacos/métodos , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Resveratrol/síntesis química , Estilbenos/síntesis química , Técnicas de Química Sintética , Teoría Funcional de la Densidad , Dimerización , Humanos , Resveratrol/análogos & derivados , EstereoisomerismoRESUMEN
Tree peonies are well-known horticultural and medicinal plants. The tree peony seeds, as emerging woody oil crops, recently have attracted great attention for their metabolites and bioactivities. In this study, the phytochemicals isolated from tree peony seed coats were systematically investigated. Seven polyphenolics were separated and prepared, mainly belonging to resveratrol derivatives. There was a great variation in the seed coat polyphenolic content among eight Paeonia species, and the contents of the resveratrol trimers and dimers were significantly higher in the seed coats of Paeonia ostii than other species. Based on the HPLC fingerprint characteristics and chemometric analysis, a clear discrimination among Paeonia plants was found, including the composition patterns and contents of the constituents. Moreover, the characteristic phytochemicals (vateriferol and trans-ε-viniferin) could significantly reduce the starch-mediated levels of postprandial blood glucose in diabetic/normal mice. In addition, in vitro enzyme tests showed that the two compounds could effectively and competitively inhibit α-glucosidase, with the IC50 values of 3.01 and 7.75 µM, respectively, indicating that vateriferol and trans-ε-viniferin could be therapeutic potential agents for hyperglycemia and diabetes mellitus.
Asunto(s)
Glucemia/efectos de los fármacos , Paeonia/química , Resveratrol/análogos & derivados , Resveratrol/farmacología , Semillas/química , Animales , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Resveratrol/química , Almidón/administración & dosificación , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismoRESUMEN
The persistence of HIV-1 latent reservoir creates the major obstacle toward an HIV-1 cure. The "shock and kill" strategy aims to reverse HIV-1 proviral latency using latency-reversing agents (LRAs), thus boosting immune recognition and clearance to residual infected cells. Unfortunately, to date, none of these tested LRA candidates has been demonstrated effectiveness and/or safety in reactivation HIV-1 latency. The discovery and development of effective, safe and affordable LRA candidates are urgently needed for creating an HIV-1 functional cure. Here, we designed and synthesized a series of small-molecule phenoxyacetic acid derivatives based on the resveratrol scaffold and found one of them, named 5, 7-dimethoxy-2-(5-(methoxymethyl) furan-2-yl) quinazolin-4(3H)-one (Q205), effectively reactivated latent HIV-1 in latent HIV-1-infected cells without a corresponding increase in induction of potentially damaging cytokines. The molecular mechanism of Q205 is shown to increase the phosphorylation of the CDK9 T-loop at position Thr186, dissociate positive transcription elongation factor b (P-TEFb) from BRD4, and promote the Tat-mediated HIV-1 transcription and RNA polymerase II (RNAPII) C-terminal domain (CTD) on Ser (CTD-Ser2P) to bind to the HIV-1 promoter. This study provides a unique insight into resveratrol modified derivatives as promising leads for preclinical LRAs, which in turn may help toward inhibitor design and chemical optimization for improving HIV-1 shock-and kill-based efforts.
Asunto(s)
VIH-1/efectos de los fármacos , VIH-1/metabolismo , Factor B de Elongación Transcripcional Positiva/metabolismo , Resveratrol/análogos & derivados , Resveratrol/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Células Jurkat , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismoRESUMEN
Imine resveratrol analogs (IRAs) are promising new agents that can have higher positive effects and, simultaneously, lower negative properties than resveratrol. In this study, three imine hydroxy derivatives (2-((4-hydroxyphenylimino) methyl) phenol [IRA1], 3-((4-hydroxyphenylimino) methyl) phenol [IRA2], and 4-((4-hydroxyphenylimino) methyl) phenol [IRA3]) were prepared and tested in several biological assays. They performed superior to resveratrol in several antioxidant and biological assays, showing high antioxidant capacity and low genotoxicity. Ferric reducing antioxidant power assay (FRAP) and hydroxyl radicals scavenging assay revealed good Fe3+ to Fe2+ reduction and strong inhibition of hydroxyl radical formation, respectively. High dosage (1 mmol/dm3 ) of IRA2 and IRA3 did not cause genotoxicity in human lymphocytes. Moreover, lymphocytes pretreated with all three IRAs accumulated only very few DNA breaks induced by H2 O2 than lymphocytes pretreated with resveratrol. Additionally, the number of detected DNA breaks appearing after removal of damaged DNA bases, 8-oxo-7,8-dihydroguanine (8-oxoG), did not dramatically increase in lymphocytes treated with IRA2. Thus, we concluded that IRAs, especially IRA2, are strong antioxidants with the ability to protect lymphocytes from oxidative damage.
Asunto(s)
Antioxidantes , Linfocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Resveratrol , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Humanos , Resveratrol/análogos & derivados , Resveratrol/síntesis química , Resveratrol/química , Resveratrol/farmacologíaRESUMEN
It is commonly known that radiotherapy is still a key modality for treatment of cancer. Though this effect is desirable during radiotherapy, it leads to radiotoxicity on normal healthy cells. In the present research, we designed, synthesized and analyzed a series of nitronyl nitroxide radical (NITR) spin-labeled resveratrol (RES) derivatives. The cytotoxicity of the newly synthesized substances was tested on Jurkat T cells. The derivatives were studied as reactive oxygen species (ROS) scavenger to protect ionizing radiation of Jurkat T cells upon 6 Gy X-irradiation. The experimental results revealed that compound 2 and 3 could significantly alleviate the damage of Jurkat T cells, as evidenced by decreasing ROS production and restoring the cell apoptosis. Further mechanism investigations indicated that the radioprotective effects of the novel derivatives were largely associated with modulating the expression of apoptotic proteins including cIAP-1, cIAP-2, cytochrome c, caspase-3 and caspase-9. Based on the experimental result, we disclosed that the novel NITR spin-labeled RES derivatives exhibit the potential to be used as the novel radioprotective candidates to ameliorate the injury induced by ionizing radiation.
Asunto(s)
Apoptosis/efectos de los fármacos , Óxidos de Nitrógeno/farmacología , Protectores contra Radiación/farmacología , Resveratrol/farmacología , Antioxidantes/farmacología , Humanos , Células Jurkat , Estructura Molecular , Radiación Ionizante , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/análogos & derivados , Marcadores de SpinRESUMEN
Acute myeloid leukemia is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Despite recent advances in the treatment of this disease, the prognosis and overall long-term survival for patients remain poor, which drives the search for new chemotherapeutics and treatment strategies. Piceatannol, a polyphenolic compound present in grapes and wine, appears to be a promising chemotherapeutic agent in the treatment of leukemia. The aim of the present study was to examine whether piceatannol induces autophagy and/or apoptosis in HL-60 human acute myeloid leukemia cells and whether HL-60 cells are able to acquire resistance to piceatannol toxicity. We found that piceatannol at the IC90 concentration of 14 µM did not induce autophagy in HL-60 cells. However, it induced caspase-dependent apoptosis characterized by phosphatidylserine externalization, disruption of the mitochondrial membrane potential, caspase-3 activation, internucleosomal DNA fragmentation, PARP1 cleavage, chromatin condensation, and fragmentation of cell nuclei. Our findings also imply that HL-60 cells are able to acquire resistance to piceatannol toxicity via mechanisms related to MRP1 activity. Our results suggest that the use of piceatannol as a potential chemotherapeutic agent may be associated with the risk of multidrug resistance, warranting its use in combination with other chemotherapeutic agents.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Leucemia Mieloide Aguda/metabolismo , Resveratrol/análogos & derivados , Estilbenos/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Autofagia/efectos de los fármacos , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Células HL-60 , Humanos , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Estilbenos/químicaRESUMEN
Radiotherapy is among the most important methods for breast cancer treatment. However, this method's effectiveness is limited by radioresistance. The aim of this study was to investigate whether the stilbene derivatives piceid, resveratrol, and piceatannol have a radiosensitising effect on breast cancer cells (MCF-7). The conducted research enabled us to determine which of the tested compounds has the greatest potential in sensitising cells to ionising radiation (IR). Among the stilbene derivatives, resveratrol significantly increased the effect of IR. Resveratrol and IR used in combination had a higher cytotoxic effect on MCF-7 cells than using piceatannol, piceid, or radiation alone. This was due to a significant decrease in the activity of antioxidant enzymes, which resulted in the accumulation of formed reactive oxygen species (ROS). The effect of resveratrol and IR enhanced the expression of apoptotic genes, such as Bax, p53, and caspase 8, leading to apoptosis.
Asunto(s)
Neoplasias de la Mama , Glucósidos/farmacología , Tolerancia a Radiación/efectos de los fármacos , Radiación Ionizante , Resveratrol , Estilbenos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Femenino , Humanos , Células MCF-7 , Resveratrol/análogos & derivados , Resveratrol/farmacologíaRESUMEN
Plant diseases caused by plant viruses and pathogens seriously affect crop yield and quality, and it is very difficult to control them. The discovery of new leads based on natural products is an important way to innovate pesticides. Based on the resveratrol is a kind of natural phytoalexin, but it cannot be used as candidate for the development of new drug due to its poor druggability. The phenolic hydroxyl groups in the resveratrol structure are easily destroyed by oxidation, in order to improve its stability, ester formation is the most commonly used modification method in drug design. Their structures were characterized by 1H NMR, 13C NMR and HRMS. The activity against tobacco mosaic virus (TMV) of these ester derivatives has been tested for the first time. The bioassay results showed part of the target compounds exhibited good to excellent in vivo activities against TMV. The optimum compounds III-2 (inhibitory rates of 50, 53, and 59% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively), III-4 (inhibitory rates of 57, 59, and 51% at 500 µg/mL, respectively), and II-5 (inhibitory rates of 54, 52, and 51% at 500 µg/mL, respectively) displayed higher activity than commercial plant virucide ribavirin (inhibitory rates of 38, 37, and 40% at 500 µg/mL, respectively). Compounds I-9 and I-10 also showed excellent activities. The systematic study provides strong evidence that these simple resveratrol derivatives could become potential TMV inhibitors. The novel concise structure provides another new template for antiviral studies.
Asunto(s)
Antifúngicos/farmacología , Antivirales/farmacología , Resveratrol/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Insecticidas/farmacología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/terapia , Enfermedades de las Plantas/virología , Resveratrol/análogos & derivadosRESUMEN
Resveratrol (RES) has a low bioavailability. This limitation was addressed in an earlier review and several recommendations were offered. A literature search was conducted in order to determine the extent of the research that was conducted in line with these recommendations, along with new developments in this field. Most of the identified studies were pre-clinical and confirmed the heightened activity of RES analogues compared to their parent compound. Although this has provided additional scientific kudos for these compounds and has strengthened their potential to be developed into phytopharmaceutical products, clinical trials designed to confirm this increased activity remain lacking and are warranted.
Asunto(s)
Resveratrol , Animales , Disponibilidad Biológica , Humanos , Resveratrol/análogos & derivados , Resveratrol/química , Resveratrol/farmacocinéticaRESUMEN
The methylated resveratrol analogue 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214) has been revealed to exert the anti-cancer activity by a block of the cell cycle at the G2/M phase, apoptosis induction, and metastasis inhibition. These biological events may be involved in crosstalk with the epidermal growth factor receptor (EGFR), which belongs to the ErbB family of receptor tyrosine kinases. Several cancer therapeutic approaches employ small molecules capable of inhibiting tyrosine kinases (e.g., gefitinib). According to more recent reports, combining gefitinib with chemotherapeutics, such as cisplatin, seems to be more effective than monotherapy. The present study aimed to assess the molecular mechanism of the potential anti-proliferative activity of individual and combined treatments with DMU-214 and gefitinib in SCC-25 and CAL-27 human tongue cancer cell lines. We showed for the first time the anti-cancer effects of DMU-214, gefitinib, and their combination in tongue cancer cells triggered via cell cycle arrest, apoptosis induction, and inhibition of the EGFR signaling pathway. The anti-proliferative effects of DMU-214 and gefitinib are also suggested to be related to the EGFR and EGFRP (phosphorylated epidermal growth factor receptor) expression status since we found significantly weaker cytotoxic activity of the compounds tested in SCC-25 cells, which overexpressed EGFR and EGFRP proteins.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Lengua/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ciclo Celular , Proliferación Celular , Receptores ErbB/antagonistas & inhibidores , Gefitinib/administración & dosificación , Humanos , Resveratrol/administración & dosificación , Resveratrol/análogos & derivados , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/metabolismo , Células Tumorales CultivadasRESUMEN
Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Resveratrol/farmacología , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Resveratrol/análogos & derivadosRESUMEN
Resveratrol can affect the physiology or biochemistry of offspring in the maternal-fetal animal model. However, it exhibits low bioavailability in humans and animals. Fifteen-week SD pregnant female rats were orally administered bisphenol A (BPA) and/or resveratrol butyrate ester (RBE), and the male offspring rats (n = 4-8 per group) were evaluated. The results show that RBE treatment (BPA + R30) compared with the BPA group can reduce the damage caused by BPA (p < 0.05). RBE enhanced the expression of selected genes and induced extramedullary hematopoiesis and mononuclear cell infiltration. RBE increased the abundance of S24-7 and Adlercreutzia in the intestines of the male offspring rats, as well as the concentrations of short-chain fatty acids (SCFAs) in the feces. RBE also increased the antioxidant capacity of the liver by inducing Nrf2, promoting the expression of HO-1, SOD, and CAT. It also increased the concentration of intestinal SCFAs, enhancing the barrier formed by intestinal cells, thereby preventing BPA-induced metabolic disruption in the male offspring rats, and reduced liver inflammation. This study identified a potential mechanism underlying the protective effects of RBE against the liver damage caused by BPA exposure during the peri-pregnancy period, and the influence of the gut microbiota on the gut-liver axis in the offspring.
Asunto(s)
Compuestos de Bencidrilo/efectos adversos , Hepatopatías/prevención & control , Fenoles/efectos adversos , Resveratrol/farmacología , Animales , Antioxidantes/metabolismo , Compuestos de Bencidrilo/farmacología , Butiratos/metabolismo , Ésteres/metabolismo , Ácidos Grasos Volátiles/metabolismo , Femenino , Microbioma Gastrointestinal , Hígado/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Masculino , Fenoles/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Sprague-Dawley , Resveratrol/análogos & derivadosRESUMEN
Resveratrol and quercetin are among the most studied plant polyphenols, and have many health-promoting actions. Strategies to accumulate them into mitochondria may be of therapeutic relevance, since these compounds are redox active and are well known to impact mitochondria and mitochondrial proteins. We report here the procedures to synthesize mitochondria-targeted resveratrol and quercetin derivatives; the synthetic strategies reported are however expected to be adaptable to other polyphenols with similar reactivity at the phenolic hydroxyls. Mitochondrial targeting can be achieved by conjugation with triphenylphosphonium , a lipophilic cation; this was linked via a butyl spacer forming an ether bond with one of the phenolic oxygens. The first step toward the synthesis of all mitochondriotropic derivatives described in this work is the production of a regiospecific -(4-O-chlorobutyl) derivative. Triphenylphosphonium (P+Ph3I-) is then introduced through two consecutive nucleophilic substitution steps: -Cl â -I â -P+Ph3I-. Pure mono-substituted chlorobutyl regioisomers are obtained by purification from the reaction mixture in the case of resveratrol , while specific protection strategies are required for quercetin to favor alkylation of one specific hydroxyl.Functionalization of the remaining hydroxyls can be exploited to modulate the physicochemical properties of the derivatives (i.e., water solubility, affinity for cell membranes); we report here synthetic protocols to obtain acetylated and methylated analogs.A brief description of some methods to assess the accumulation of the derivatives in mitochondria is also given; the proposed techniques are the use of a TPP +-selective electrode (with isolated rat liver mitochondria ) and fluorescence microscopy (with cultured cells).
Asunto(s)
Mitocondrias Hepáticas/química , Polifenoles/síntesis química , Quercetina/análogos & derivados , Resveratrol/análogos & derivados , Animales , Células HCT116 , Humanos , Mitocondrias Hepáticas/efectos de los fármacos , Estructura Molecular , Compuestos Organofosforados/química , Polifenoles/química , Polifenoles/farmacología , RatasRESUMEN
Numerous studies have shown that resveratrol can induce apoptosis in cancer cells. Trans-3, 5, 4'-trimethoxystilbene (TMS), a novel derivative of resveratrol, is a more potent anticancer compound than resveratrol and can induce apoptosis in cancer cells. Herein, we examined the mechanisms involved in TMS-mediated sensitization of human osteosarcoma (143B) cells to TNF-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis. Our results showed that cotreatment with TSM and TRAIL activated caspases and increased PARP-1 cleavage in 143B cells. Decreasing cellular ROS levels using NAC reversed TSM- and TRAIL-induced apoptosis in 143B cells. NAC abolished the upregulated expression of PUMA and p53 induced by treatment with TRAIL and TSM. Silencing the expression of p53 or PUMA using RNA interference attenuated TSM-mediated sensitization of 143B cells to TRAIL-induced apoptosis. Knockdown of Bax also reversed TSM-induced sensitization of 143B cell to TRAIL-mediated apoptotic cell death. These results indicate that cotreatment with TRAIL and TSM evaluated intracellular ROS level, promoted DNA damage, and activated the Bax/PUMA/p53 pathway, leading to activation of both mitochondrial and caspase-mediated apoptosis in 143B cells. Orthotopic implantation of 143B cells in mice also demonstrated that cotreatment with TRAIL and TSM reversed resistance to apoptosis in cells without obvious adverse effects in normal cells.