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J Nat Prod ; 82(4): 823-831, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30840453


The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1ß2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.

J Med Chem ; 62(1): 317-341, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30289721


Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the ß2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [( E)-2-Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents ( Emax: 3114 ± 242%), while 12 [( Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 µM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protection against pentylenetetrazole (PTZ)-induced seizures compared to VA and LOR. Collectively, compound 12 constitutes a novel, simplified, and subunit-selective GABAAR modulator with low-dose anticonvulsant activity.

Amidas/química , Anticonvulsivantes/síntese química , Desenho de Fármacos , Receptores de GABA-A/química , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/uso terapêutico , Feminino , Hipocampo/metabolismo , Indenos/química , Oocistos/metabolismo , Técnicas de Patch-Clamp , Pentilenotetrazol/toxicidade , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/patologia , Sesquiterpenos/química , Relação Estrutura-Atividade , Triazóis/química , Xenopus laevis/metabolismo
Planta Med ; 83(14-15): 1169-1175, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28511229


A dichloromethane extract from leaves of Searsia pyroides potentiated gamma aminobutyric acid-induced chloride currents by 171.8 ± 54% when tested at 100 µg/mL in Xenopus oocytes transiently expressing gamma aminobutyric acid type A receptors composed of α1ß2γ2s subunits. In zebrafish larvae, the extract significantly lowered pentylenetetrazol-provoked locomotion when tested at 4 µg/mL. Active compounds of the extract were tracked with the aid of HPLC-based activity profiling utilizing a previously validated zebrafish larval locomotor activity assay. From two active HPLC fractions, compounds 1 - 3 were isolated. Structurally related compounds 4 - 6 were purified from a later eluting inactive HPLC fraction. With the aid of 1H and 13C NMR and high-resolution mass spectrometry, compounds 1 - 6 were identified as analogues of anacardic acid. Compounds 1 - 3 led to a concentration-dependent decrease of pentylenetetrazol-provoked locomotion in the zebrafish larvae model, while 4 - 6 were inactive. Compounds 1 - 3 enhanced gamma aminobutyric acid-induced chloride currents in Xenopus oocytes in a concentration-dependent manner, while 4 - 6 only showed marginal enhancements of gamma aminobutyric acid-induced chloride currents. Compounds 2, 3, and 5 have not been reported previously.

Anacardiaceae/química , Ácidos Anacárdicos/farmacologia , GABAérgicos/farmacologia , Extratos Vegetais/farmacologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ácidos Anacárdicos/química , Ácidos Anacárdicos/isolamento & purificação , Animais , Bioensaio , Cloretos , Cromatografia Líquida de Alta Pressão , GABAérgicos/química , GABAérgicos/isolamento & purificação , Larva , Locomoção/efeitos dos fármacos , Cloreto de Metileno , Oócitos , Pentilenotetrazol , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Xenopus laevis , Peixe-Zebra
Food Chem ; 170: 154-9, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25306330


For the provision of oleocanthal (OLC), a phenolic compound with very promising pharmacological properties, isolation from olive oil is a very important option. Due to the compound's sensitivity to decomposition upon exposure to oxygen and light, a very gentle isolation method has been developed under use of high performance countercurrent chromatography (HPCCC). By partition of olive oil between hexane and methanol, an extract enriched in phenolics was prepared and subjected to a two-step HPCCC separation under use of heptane-EtOAc-MeOH-H2O mixtures in normal-phase and reverse phase mode, respectively. With this method, the isolation of tyrosol, hydroxytyrosol, and the mixture of (3S,4E)- and (3S,4Z)-OLC was achieved in approx. 70 min for each step. By one- and two-dimensional NMR-experiments and LC-MS, the equilibrium of (3S,4E)- and (3S,4Z)-OLC in such olive oil extracts has unambiguously been proven for the first time.

Aldeídos/química , Distribuição Contracorrente/métodos , Azeite de Oliva/análise , Fenóis/química , Álcool Feniletílico/análogos & derivados , Óleos Vegetais/análise , Cromatografia Líquida de Alta Pressão/métodos , Monoterpenos Ciclopentânicos , Álcool Feniletílico/química , Óleos Vegetais/química