RESUMEN
Natural xanthones are a large group of compounds from which promising anticancer properties could be further developed by chemical modifications. This study aimed to investigate the influence of four novel xanthone derivatives based on a naturally occurring xanthone skeleton on the invasiveness of colon cancer cells in vitro. First, the concentrations required to inhibit growth of three colorectal cancer cell lines to 50% (GI50) of all the studied compounds, as well as the natural xanthones used as a reference (gambogic acid and α-mangostin), have been established (MTS reduction test). Next, the assays determining several aspects of the GI25 xanthones influence on colorectal cancer cells, including cytotoxicity, migration and invasion potential, interaction with extracellular matrix and endothelial cells, as well as expression of selected invasiveness related genes have been performed. Our results demonstrate that these novel xanthone derivatives impair colorectal cancer proliferation, motility, adhesion to extracellular matrix and to endothelial cells, and also induce apoptosis and cell death. Moreover, their activity is comparable to cisplatin and 5-fluorouracil, used as reference compounds. Conducted research indicates our compounds for further research and development as novel drugs in colorectal cancer treatment.
Asunto(s)
Neoplasias del Colon/patología , Xantonas/farmacología , Apoptosis/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Clonales , Neoplasias del Colon/genética , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Factor A de Crecimiento Endotelial Vascular/metabolismo , Xantonas/químicaRESUMEN
BACKGROUND: Our previous studies showed that xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 (R, S) and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity. AIMS: We aimed to assess the in vitro and in vivo pharmacological activity of the xanthone derivatives. METHODS: We evaluated the in vitro affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25-20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters. RESULTS: Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca2+ mobilization assay; however, they showed significant agonistic properties in the ß-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood-brain barrier and had a relatively high bioavailability after intraperitoneal administration. CONCLUSIONS: Xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.
Asunto(s)
Antidepresivos/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología , beta-Arrestinas/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacocinética , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Xantonas/administración & dosificación , Xantonas/farmacocinéticaRESUMEN
BACKGROUND: Natural plant metabolites and their semisynthetic derivatives have been used for years in cancer therapy. Xanthones are oxygenated heterocyclic compounds produced as secondary metabolites by higher plants, fungi or lichens. Xanthone core may serve as a template in the synthesis of many derivatives that have broad biological activities. OBJECTIVE: This study synthesized a series of 17 new xanthones, and their anticancer potential was also evaluated. METHODS: The anticancer potential was evaluated in vitro using a highly invasive T24 cancer cell line. Direct cytotoxic effects of the xanthones were established by IC50 estimation based on XTT assay. RESULTS: 5 compounds of the total 17 showed significant cytotoxicity toward the studied cancer cultures and were submitted to further detailed analysis, including studies examining their influence on gelatinase A and B expression, as well as on the cancer cells migration and adhesion to an extracellular matrix. These analyses were carried out on five human tumor cell lines: A2780 (ovarian cancer), A549 (lung cancer), HeLa (cervical cancer), Hep G2 (liver cancer), and T24 (urinary bladder cancer). All the compounds, especially 4, showed promising anticancer activity: they exhibited significant cytotoxicity towards all the evaluated cell lines, including MCF-7 breast cancer, and hindered migration-motility activity of cancer cells demonstrating more potent activity than α-mangostin which served as a reference xanthone. CONCLUSION: These results suggest that our xanthone derivatives may be further analyzed in order to include them in cancer treatment protocols.
Asunto(s)
Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Xantonas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Estructura Molecular , Xantonas/química , Xantonas/farmacologíaRESUMEN
The aim of this study was to evaluate antifungal activity in a diverse group of chlorine-containing xanthone and phenoxyethyl amine derivatives - and to select the most promising compounds for further studies. The antifungal efficacy of 16 compounds was tested with qualitative and quantitative methods against both reference and clinical strains of dermatophytes, moulds and yeasts. The disc-diffusion method has demonstrated that from 16 tested compounds, 7 possess good antifungal activity against dermatophytes and/or moulds while none of them has shown good efficacy against yeasts or bacterial strains. The most active compounds (2, 4, 10, 11, 12, 15, 16) were tested quantitatively by broth dilution method to obtain MIC values. The MIC values against dermatophytes ranged from 8 to 64 µg/ml. Compound 2 was the most active one against dermatophytes (MIC 50 and MIC 90 were 8 µg/ml). The MIC values for moulds ranged from 16 to 256 µg/ml. Compound 4 was the most active one against moulds, with MIC 50 and MIC 90 values amounting to 32 µg/ml. Among the tested compounds, compound 4 (derivative of xanthone) was the most active one and expressed good antifungal efficacy against clinical strains of dermatophytes and moulds. However, another xanthone derivative (compound 2) was the most active and selective against dermatophytes.
Asunto(s)
Aminas/química , Antifúngicos/química , Cloro/química , Xantonas/química , Aminas/síntesis química , Aminas/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Arthrodermataceae/efectos de los fármacos , Aspergillus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Trichophyton/efectos de los fármacos , Xantonas/síntesis química , Xantonas/farmacologíaRESUMEN
Reactive oxygen species (ROS) are critically involved in the action of anticancer agents. In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence. We also observed that mitochondrial dysfunction and cellular apoptosis enhancement correlated with xanthone-induced oxidative stress. Finally, we showed that the use of the antioxidant N-acetyl-L-cysteine partly reversed these effects of aminoalkanol xanthones. Our results demonstrated that novel aminoalkanol xanthones mediated their anticancer activity primarily through ROS elevation and enhanced oxidative stress, which led to mitochondrial cell death stimulation; this mechanism was similar to the activity of gambogic acid.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Xantonas/farmacología , Acetilcisteína/farmacología , Aminas/química , Animales , Antineoplásicos/química , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Línea Celular , Senescencia Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Glutatión Peroxidasa/metabolismo , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Superóxido Dismutasa/metabolismo , Xantonas/química , beta-Galactosidasa/metabolismoRESUMEN
Because of numerous indications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used medicines in the world. However, long-term therapy with and improper use of NSAIDs may lead to gastrointestinal damage. Therefore, improving the therapeutic index of the existing drugs has become a priority over the past decades. Considerable attention in the field has been concentrated on metal complexes of non-steroidal anti-inflammatory drugs. The aim of this study is to evaluate the effect of complexation with zinc on the anti-inflammatory and ulcerogenic effects of ibuprofen and naproxen after single and triple intragastric administration to rats. The anti-inflammatory effect was assessed in carrageenan-induced inflammatory edema in the hind paw of male albino Wistar rats. The mucosal lesions were inspected and evaluated for gross pathology. Single administration of both the investigated complexes, namely zinc-ibuprofen and zinc-naproxen (20 mg/kg equivalent to ibuprofen and naproxen, respectively) and their parent drugs and physical mixtures with zinc hydroaspartate (ZHA doses: 16.05 and 14.37 mg/kg), caused a significant reduction of the edema after the same time from the carrageenan injection in comparison to the control groups. However, no statistically significant differences between the investigated drugs were observed after their single administration. The mean ulceration score for the mixture of ibuprofen and ZHA was statistically lower than the mean score achieved in rats after treatment with ibuprofen alone. On the other hand, triple intragastric administration of the ZHA-ibuprofen and ZHA-naproxen combination showed substantial enhancement of the anti-inflammatory activity against control groups, as well as against the parent NSAIDs. The most potent anti-inflammatory activity was demonstrated after 2 h from the carrageenan injection in animals receiving ZHA together with naproxen. The edema growth was reduced in these animals by 80.9% as compared to the control group. This result was significantly higher than the results achieved in animals receiving zinc-naproxen (50.2%) or naproxen alone (47.9%). Both NSAID complexes with zinc and mixtures with ZHA alleviated ulcerations caused by parent NSAIDs; however, the mixtures of both ibuprofen and naproxen with ZHA after triple administration were the least damaging. In view of the above results, zinc supplementation during NSAID therapy may have a beneficial effect on ulcer prevention and healing by reducing the effective dose of the parent drug and increasing its potency.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Mucosa Gástrica/efectos de los fármacos , Ibuprofeno/farmacología , Inflamación/tratamiento farmacológico , Naproxeno/farmacología , Zinc/farmacología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacología , Carragenina/farmacología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ibuprofeno/efectos adversos , Inflamación/inducido químicamente , Masculino , Naproxeno/efectos adversos , Compuestos Organometálicos/farmacología , Ratas , Ratas Wistar , Compuestos de Zinc/farmacologíaRESUMEN
This in vitro study was designed to examine the effect of some newly synthesized aminoalcanolic derivatives of xanthone (I, II) and aroxyalkyl derivatives of 2-methoxyphenylpiperazine (III, IV) having cardiovascular activity on the haemorheological parameters of RBCs from healthy individuals and patients with chronic venous disease. Additionally, the influence of compounds I-IV on some RBCs associated enzymes such as acetylcholinesterase (Ache), glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GR) as well as glutathione (GSH) content were determined in vitro in RBCs from healthy subjects. The study showed that compounds I, III and IV significantly increased RBCs deformability. Moreover, both xanthone derivatives reduced RBCs aggregation and diminished RBCs aggregates strength in all RBCs groups. Compounds II and III significantly improved Ache activity, whereas compounds I and II increased G6PD and GR activity and GSH level. In conclusion, compounds I, III and IV, which significantly improved RBCs deformability in vitro, may facilitate the passage of blood in the vascular system. Additionally, compounds I and II which inhibit RBCs aggregates formation in vitro may contribute to more rapid degradation of red blood cell aggregates in circulating blood.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Eritrocitos/metabolismo , Piperazinas/síntesis química , Reología/métodos , Xantonas/síntesis química , Acetilcolinesterasa/metabolismo , Agregación Eritrocitaria , Humanos , Masculino , Piperazinas/química , Xantonas/químicaRESUMEN
A series of 15 derivatives of xanthone were synthesized and evaluated for the anticancer activity. The structure of the tested compounds was diversified to establish structureactivity relationships. The following evaluations were carried out: cytotoxicity-proliferation tests, apoptosis detection, expression of apoptosis and proliferation-related genes, expression and activity of gelatinases A and B, wound migration assays, and cell adhesion to MatrigelTMcoated plates. Four compounds (7, 12, 13 and 15) displayed direct cytotoxicity at micromolar concentrations toward the studied cell lines. They also significantly affected the expression of proliferationapoptosis markers, and 13 demonstrated as strong influence as α-mangostin, that served as a natural standard in our study. These four compounds also decreased the expression and activity of gelatinases, and inhibited the migration-motility potential of cancer cells. The influence of compounds 7 and 12 on MMPs mRNA levels even exceeded the activity of α-mangostin and shRNA-mediated silencing; zymography revealed that 7, 13 and 15 were as equally active as α-mangostin, despite their higher IC50 values. The highest activity to inhibit motility and migration of cancer cells was demonstrated by 7, 12, 15, and by α-mangostin; and this was almost equal to shRNA-mediated silencing. Structural features predetermining compound activity were: substitution at position C4 instead of C2, and presence of a chlorine atom and allyl moiety. These results indicate that synthesis of aminoalkanol derivatives of xanthone may lead to successful establishment of new potential anticancer chemicals.
Asunto(s)
Amino Alcoholes/farmacología , Antineoplásicos/farmacología , Xantonas/farmacología , Amino Alcoholes/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Xantonas/síntesis química , Xantonas/químicaRESUMEN
A series of 20 xanthone derivatives was synthesized and evaluated for anti-Helicobacter pylori (H. pylori) activity. Qualitative and quantitative in vitro tests using the Kirby-Bauer method (agar disc-diffusion method) were performed. The tested compounds were screened against clarithromycin- and/or metronidazole-resistant strains of H. pylori. As a reference, Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacterial strains were examined. On the basis of microbiological assays, xanthones can be considered as potential anti-H. pylori agents. They displayed significant activity against the examined strains, which was higher against the bacteria resistant to metronidazole than clarithromycin. The lowest MIC values ranging up to 20 mg l-1 were observed for the following compounds: 3, 4, 8, 9, 12, 19 (against the metronidazole-resistant strains) and the compound 10 (against the clarithromycin-resistant strain). These preliminary results for screening of xanthone derivatives form a part of an ongoing study of the structure-activity relationships of a large group of compounds. Microbiological assays will be conducted afterwards to determine the mechanism of xanthones' action against H. pylori.
Asunto(s)
Antibacterianos/farmacología , Helicobacter pylori/efectos de los fármacos , Xantonas/farmacología , Antibacterianos/química , Claritromicina/farmacología , Metronidazol/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Xantonas/químicaRESUMEN
Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock--MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as RM0, was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S-(E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1) and R,S-(E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (3) exhibited the best anticonvulsant activity. Compound 1, when administered to mice by intraperitoneal (i.p.) injection, showed the ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p.). The distances measured in crystals of compound 1 were: 7.99 Å--from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 Å--from the phenyl ring to the amide group, and 3.112 Å--from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2).
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Convulsiones/tratamiento farmacológico , Amino Alcoholes/química , Animales , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Electrochoque/efectos adversos , Células Hep G2/efectos de los fármacos , Humanos , Inyecciones Intraperitoneales , Ratones , Pruebas de Mutagenicidad , Pentilenotetrazol/efectos adversos , Ratas , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/inducido químicamente , Convulsiones/etiología , Relación Estructura-ActividadRESUMEN
Certain xanthone derivatives, such as these present in mangosteen fruits, show strong antioxidant activity. On the other hand, evidences accumulated that oxidative stress is involved in epileptogenesis. Therefore, the aim of the present study was to estimate total antioxidant capacity (expressed as a ferric reducing antioxidant power - FRAP) and evaluate ability to scavenge free radicals (DPPH methods) by xanthone derivatives showing antiepileptic activity. Selected 2-(aminomethyl)-9H-xanthen-9-one derivatives shared structural features, such as chlorine substituent in xanthone ring and different chiral (or not) alkanol groups at the nitrogen atom. The results of antioxidant activities among racemates revealed the highest activity for compound (RIS)-3 (31.7% in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and (0.184 ± 0.003 mM Fe²âº/L) in FRAP assay. Among tested pair of enantiomers we observed that (R)-1 and (R)-2 showed higher reduction capacity ((R)-1: 0.096 ± 0.007 mM F²âº/L; (R)-2: 0.048 ± 0.005 mM Fe²âº/L, respectively) and stronger DPPH scavenging activity ((R)-1: 31 ± 3.0%; (R)-2: 29 ± 2.5%, respectively) comparing to their (S)-enantiomers and racemates.
Asunto(s)
Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Estrés Oxidativo/efectos de los fármacos , Xantonas/farmacología , Antioxidantes/química , Depuradores de Radicales Libres/química , Frutas , Garcinia mangostana/química , Estereoisomerismo , Xantonas/químicaRESUMEN
BACKGROUND: We have previously shown significant prophylactic and therapeutic antiarrhythmic activity in adrenaline-induced arrhythmia, as well as α1-adrenolytic properties of new derivatives of xanthone. Herein, we investigated their antiarrhythmic activity in the model of ischemia/reperfusion in isolated hearts. Furthermore, we assessed antioxidant activity in biochemical studies. METHODS: Antiarrhythmic activity in the model of ischemia/reperfusion in isolated perfused hearts was performed according to the Langendorff technique. Antioxidant activity was measured by lipid peroxidation level in tissue homogenate and in the FRAP assay. RESULTS: All studied compounds (MH-94, MH-99 and MH-105) showed significant antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. However, they did not demonstrate antioxidant effect, probably, because of the lack of free hydroxyl group(s) at a key position in the xanthone scaffold. CONCLUSIONS: The present study provides evidences for antiarrhythmic activity of some 2-methoxyphenylpiperazine derivatives of xanthone.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/etiología , Daño por Reperfusión Miocárdica/complicaciones , Xantonas/uso terapéutico , Animales , Antiarrítmicos/farmacología , Antioxidantes/farmacología , Corazón/efectos de los fármacos , Corazón/fisiología , Corazón/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , Piperazinas/farmacología , Piperazinas/uso terapéutico , Ratas , Xantonas/farmacologíaRESUMEN
A series of 6 derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure, the effect on blood pressor response and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Two compounds revealed nanomolar affinity for α1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals' models. They were enantiomers of previously described (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one hydrochloride and revealed similar antiarrhythmic potential in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50=0.53 mg/kg and 0.81 mg/kg, respectively). These values were lower than values obtained for reference drug urapidil. These compounds were more active in this experiment than urapidil (ED50=1.26 mg/kg). The compound 5 administered iv at doses of 0.62-2.5 mg/kg at the peak of arrhythmia prevented and/or reduced the number of premature ventricular beats in a statistically significant manner. The ED50 value was 1.20 mg/kg. The S-enantiomer (6) given at the same doses did not show therapeutic antiarrhythmic activity in this model. These compounds significantly decreased the systolic and diastolic blood pressure throughout the whole observation period in anesthetized, normotensive rats. The studied enantiomers showed higher toxicity than urapidil, but imperceptibly higher that another cardiovascular drugs, that is, carvedilol or propranolol. They were also evaluated for mutagenic potential in the Ames (Salmonella) test. It was found that at the concentrations tested the compounds were non mutagenic when compared to solvent control. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.
Asunto(s)
Antiarrítmicos/farmacología , Antihipertensivos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Xantonas/farmacología , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/química , Antihipertensivos/administración & dosificación , Antihipertensivos/química , Arritmias Cardíacas/metabolismo , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad , Xantonas/administración & dosificación , Xantonas/químicaRESUMEN
BACKGROUND: The aim of this study was to assess the selectivity of the studied xanthone derivatives for α1-adrenoceptor subtypes (α1A, α1B, α1D, α1L) in functional experiments in order to verify if they possess any selectivity for a distinct subtype of α1-adrenoceptor. Moreover, several pharmacological tests were carried out to assess whether they reveal other than α1-adrenoceptor blocking properties such as: antagonistic for 5-HT2 receptors, vasorelaxant or spasmolytic. METHODS: The influence on α1A-adrenoceptors was examined in biofunctional studies employing isolated rat vas deferens, on α1B-adrenoceptors in guinea-pig spleen, on α1D-adrenoceptors in rat aorta, and on α1L-adrenoceptors in rabbit spleen. Affinity for 5-HT2 receptors was measured in radioligand binding assay, whereas antagonistic potency for 5-HT2 receptors was studied on isolated rat aorta. Vasorelaxant effect of tested compounds was assessed in functional study employing rat aorta, whereas direct spasmolytic activity was investigated using the isolated rabbit small intestine. RESULTS: The present study provides evidences that the tested 2-methoxyphenylpiperazine xanthone derivatives are non-selective α1-adrenoceptor blockers. However, at higher concentrations the direct spasmolytic effect could enhance their hypotensive activity. The obtained results indicate that the studied xanthones possessed weak calcium entry blocking activity, as well as antagonistic properties for 5-HT2A receptors. CONCLUSIONS: The results of the present study support the idea that the hypotensive activity of the studied compounds is related to their α1-adrenolytic properties.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Piperazinas/farmacología , Xantonas/farmacología , Animales , Aorta/efectos de los fármacos , Canales de Calcio/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cobayas , Humanos , Íleon/efectos de los fármacos , Masculino , Cloruro de Potasio/farmacología , Conejos , Ensayo de Unión Radioligante , Ratas , Receptores de Serotonina 5-HT2/metabolismo , Bazo/efectos de los fármacosRESUMEN
A series of aminoalkanolic derivatives of xanthone with high affinity for ß1-adrenoceptors was evaluated for antiarrhythmic activity in the model of ischemia-reperfusion in isolated hearts, as well as in barium chloride- and adrenaline-induced model of arrhythmia. In order to better understand biological activity of studied compounds, the influence on ß2-adrenoceptors in guinea-pig trachea and vasorelaxant properties in rat aorta were evaluated. Furthermore, due to assessed antioxidant activity, some biochemical studies were also performed. All tested compounds showed prominent antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. In this experiment the most active was compound MH-97. Whereas, compound MH-82 was the most active in barium- and adrenaline-induced arrhythmia after i.v. or p.o. administration, respectively. These two compounds have higher affinity to ß1-adrenoceptors than compound MH-87, thus it suggests that blocking properties of ß1-adrenoceptors are involved in the observed antiarrhythmic effects. All studied compounds have revealed antagonistic potency for ß2-adrenoceptors in tracheal smooth muscle, however weaker than that of propranolol. None of tested compounds demonstrated antioxidant effect. They also had weak calcium entry blocking activity. The results of this study suggest that new compounds with antiarrhythmic activity might be found in the group of xanthone derivatives.
Asunto(s)
Antiarrítmicos/metabolismo , Antiarrítmicos/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Receptores Adrenérgicos beta 1/metabolismo , Xantonas/metabolismo , Xantonas/farmacología , Animales , Antiarrítmicos/química , Antiarrítmicos/uso terapéutico , Antioxidantes/química , Antioxidantes/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/fisiopatología , Atenolol/farmacología , Compuestos de Bario/farmacología , Cloruros/farmacología , Epinefrina/efectos adversos , Cobayas , Corazón/efectos de los fármacos , Corazón/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Propranolol/farmacología , Unión Proteica , Ratas , Daño por Reperfusión/fisiopatología , Tráquea/efectos de los fármacos , Tráquea/fisiología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Xantonas/química , Xantonas/uso terapéuticoRESUMEN
ß-Adrenoceptor antagonists are important drugs for the treatment of cardiovascular diseases and some of those drugs also block the so-called low-affinity site of ß1-adrenoceptors although at much higher concentrations. This low-affinity site, also identified in vivo and in human tissue, may come into play under certain pathophysiological situations including arrhythmias. The aim of our study was to determine the potency of 14 compounds chemically related to bupranolol or bevantolol and two xanthone derivatives at the low-affinity site of the ß1-adrenoceptor. The potency of the compounds at the low- and high-affinity site of ß1-adrenoceptors (ß1L and ß1H; both increasing heart rate) was compared in the pithed rat. One compound was also studied in the isolated rat heart and its α1-adrenolytic effect determined in the isolated rat mesenteric artery. In the pithed rat, four compounds blocked the ß1L-adrenoceptor at a ≥10-fold lower potency than the ß1H-adrenoceptor whereas the xanthone derivative (-)-MH-3 was equipotent. In the spontaneously beating right atrium (-)-MH-3 was a non-competitive antagonist of comparable potency at either receptor; its apparent pD'2 value for the ß1L-adrenoceptor ranged from 5.6 to 6.4 under various conditions, including the Langendorff preparation. Its apparent pA2 at the α1-adrenoceptor in the mesenteric artery was 8.4. (-)-MH-3 is the first compound with virtually the same potency at the low- and high-affinity site of ß1-adrenoceptors in vivo; it appears to be a non-competitive antagonist at either site in vitro.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Piperazinas/farmacología , Receptores Adrenérgicos beta 1/metabolismo , Xantonas/farmacología , Animales , Sitios de Unión , Corazón/efectos de los fármacos , Corazón/fisiología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Ratas WistarRESUMEN
The main goal of this study was to assess antiarrhythmic and hypotensive activity of new 2-methoxyphenylpiperazine derivatives of xanthone. In order to better understand mechanism of action of studied compounds, their abilities to antagonize the increase in blood pressure elicited by adrenaline, noradrenaline and methoxamine, as well as the antagonistic properties for α1-adrenoceptors on isolated rat aorta were evaluated. Therapeutic antiarrhythmic activity was investigated in an adrenaline-induced model of arrhythmia. Hypotensive activity in normotensive rats was evaluated after oral administration. Influence on blood vasopressor response and α1-adrenoceptors in rat thoracic aorta was evaluated to determine if the observed cardiovascular effects could be related to α1-adrenolytic properties. Tested compounds produced antiarrhythmic and hypotensive activity. The most active compound was MH-99 - (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride. All studied compounds showed α1-adrenolytic properties in the in vivo and in vitro tests. The results indicate that the new valuable compounds with antiarrhythmic and hypotensive activity might be found in the group of xanthone derivatives. Further pharmacological utility of these compounds should be investigated.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antiarrítmicos/farmacología , Antihipertensivos/farmacología , Piperazinas/farmacología , Xantonas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Animales , Antiarrítmicos/uso terapéutico , Antihipertensivos/uso terapéutico , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Epinefrina , Técnicas In Vitro , Masculino , Piperazinas/uso terapéutico , Ratas Wistar , Receptores Adrenérgicos alfa 1/fisiología , Xantonas/uso terapéuticoRESUMEN
The phosphoenolpyruvate phosphotransferase system (PTS) is ubiquitous in eubacteria and absent from eukaryotes. The system consists of two phosphoryl carriers, enzyme I (EI) and the histidine-containing phosphoryl carrier protein (HPr), and several PTS transporters, catalyzing the concomitant uptake and phosphorylation of several carbohydrates. Since a deficiency of EI in bacterial mutants lead to severe growth defects, EI could be a drug target to develop antimicrobial agents. We used the 3D structure PDB 1ZYM of Escherichia coli EI as the target to virtually screen the potential tight binders from NPPEDIA (Natural Product Encyclopedia), ZINC and Super Natural databases. These databases were screened using the docking tools of Discovery Studio 2.0 and the Integrated Drug Design System IDDS. Among the many interesting hits, xanthone derivatives with reasonably high Dock scores received more attentions. Two of the xanthone derivatives were obtained to examine their capabilities to inhibit cell growth of both Gram-positive and Gram-negative bacterial strains. The results indicate that they may exert the inhibition effects by blocking the EI activities. We have demonstrated for the first time that the xanthone derivatives have high potential to be developed as future antibiotics.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/antagonistas & inhibidores , Fosfotransferasas (Aceptor del Grupo Nitrogenado)/antagonistas & inhibidores , Xantonas/farmacología , Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Bases de Datos Factuales , Diseño de Fármacos , Inhibidores Enzimáticos/química , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Xantonas/químicaRESUMEN
A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.
Asunto(s)
Anticonvulsivantes/química , Xantonas/química , Animales , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/toxicidad , Canales de Calcio/química , Canales de Calcio/metabolismo , Electrochoque , Inyecciones Intraperitoneales , Ratones , Neuronas/efectos de los fármacos , Pentilenotetrazol/uso terapéutico , Pentilenotetrazol/toxicidad , Convulsiones/tratamiento farmacológico , Convulsiones/prevención & control , Relación Estructura-Actividad , Xantonas/uso terapéutico , Xantonas/toxicidadRESUMEN
A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α(1)-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals' models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED(50) value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED(50) = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.