RESUMO
In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with γ-aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 µM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Ansiolíticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ansiolíticos/química , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Sistema Nervoso Central/metabolismo , Células HEK293 , Humanos , Lignanas/química , Lignanas/farmacologia , Magnolia/química , Norepinefrina/metabolismo , Casca de Planta/química , Extratos Vegetais/química , Receptores de GABA-A/efeitos dos fármacosRESUMO
In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4'-O-methylhonokiol, AMH) as a high efficient modulator of GABAA receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on α1ß2γ2S GABAA receptors. The strongest IGABA enhancement was induced by compound 5 (3-acetamido-4'-ethoxy-3',5-dipropylbiphenyl-2-ol, Emax: 123.4±9.4% of IGABA-max) and 6 (5'-amino-2-ethoxy-3',5-dipropylbiphenyl-4'-ol, Emax: 117.7±13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50=1.8±1.1 µM) than compound 6 (EC50=20.4±4.3 µM). Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78±6% of IGABA-max), AMH (63±6%), 5'-amino-2-O-methylhonokiol (1) (59±1%) and 2-methoxy-5'-nitro-3',5-dipropylbiphenyl-4'-ol (3) (52±1%). 3-N-Acetylamino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (5) and 3-amino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (7) were less efficacious but even more potent (5: EC50=6.9±1.0 µM; 7: EC50=33.2±5.1 µM) than the full agonist GABA.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Agonismo Parcial de Drogas , Agonistas de Receptores de GABA-A/farmacologia , Lignanas/farmacologia , Nitrogênio/química , Receptores de GABA-A/metabolismo , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Feminino , Agonistas de Receptores de GABA-A/síntese química , Agonistas de Receptores de GABA-A/química , Lignanas/síntese química , Lignanas/química , Magnolia/química , Estrutura Molecular , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Relação Estrutura-Atividade , Xenopus laevisRESUMO
Biphenyl neolignans such as honokiol and magnolol, which are the major active constituents of the Asian medicinal plant Magnolia officinalis, are known to exert a multitude of pharmacological and biological activities. Among these, cytotoxic and tumor growth inhibitory activity against various tumour cell lines are well-documented. To further elucidate the cytotoxic effects of honokiol derivatives, derivatizations were performed using tetrahydrohonokiol as a scaffold. The derivatizations comprised the introduction of functional groups, e.g., nitro and amino groups, as well as alkylation. This way, 18 derivatives, of which 13 were previously undescribed compounds, were evaluated against CCRF-CEM leukemia cells, U251 glioblastoma and HCT-116 colon cancer cells. The results revealed no significant cytotoxic effects in any of the three tested cell lines at a test concentration of 10 µM.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Compostos de Bifenilo/síntese química , Lignanas/síntese química , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma , Células HCT116 , Humanos , Concentração Inibidora 50 , Leucemia , Lignanas/farmacologia , Metilação , Micro-OndasRESUMO
The food component 5-hydroxymethylfurfural is supposed to have antioxidative properties and is therefore used as an acting agent in a novel anticancer infusion solution, named Karal®, and an oral supplementation. Previous studies showed that after oral and intravenous application, the substance is completely decomposed to its metabolites: 5-hydroxymethylfuroic acid, 2,5-furandicarboxylic acid, and N-(hydroxymethyl)furoyl glycine. The formation of a fourth metabolite, namely 5-sulphoxymethylfurfural, is still not clarified according to literature. Due to commercial unavailability, synthesis of 5-sulphoxymethylfurfural was conducted and a synthesis procedure for N-(hydroxymethyl)furoyl glycine had to be developed. Identification of the synthesised compounds was proven by LC-MS and NMR. An appropriate HPLC method was established to obtain good separation of the four possible metabolic substances and 5-hydroxymethylfurfural within 12 min via a HILIC column (150 × 4.6 mm, 5 µm) using a gradient grade system switching from mobile phase A (ACN/ammonium formate 100 mM, pH 2.35, 95:5, v/v) to mobile phase B (ACN/ammonium formate 100 mM, pH 2.35, 85:15, v/v). The procedure was afterward validated following ICH guidelines in terms of selectivity, linearity, precision, LOD, and LOQ.