RESUMO
An efficient green approach for the trapping of in situ generated ortho-and para-quinone methide intermediates by imidazoles and pyrazoles has been developed. A wide range of quinone methide precursors based on simple phenols are compatible with the experimental protocol under mild thermal conditions. This methodology was demonstrated to be suitable for the synthesis of methylene-linked benzopyrone-azole hybrids using naturally occurring coumarin and chromone Mannich bases. In most cases, the products were isolated in good to excellent yields without chromatographic purification. In vitro studies showed that some of the synthesized compounds exhibit inhibitory activity towards α-glucosidase.
RESUMO
The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.
Assuntos
Inibidores Enzimáticos/química , Glicogênio Sintase/antagonistas & inibidores , Imidazóis/química , Pirazóis/química , Animais , Caenorhabditis elegans/enzimologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glicogênio Sintase/química , Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Cinética , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-AtividadeRESUMO
A reliable method for the synthesis of B-ring hydroxylated homoisoflavonoids and 3-hetarylmethyl chromones has been developed. The method involves an initial oxa-Diels-Alder reaction of ortho-quinone methides generated from aryl/hetaryl-substituted ortho-( N, N-dimethylaminomethyl)phenols with (2 E)-3-( N, N-dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones and the subsequent cascade of reactions. This synthetic strategy avoids conventional multistep protocols and does not require the protection of hydroxyl groups, thus allowing the facile synthesis of a library of various aromatic and heterocyclic analogues of naturally occurring homoisoflavonoids.
RESUMO
The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6-substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 µm concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.
Assuntos
Antineoplásicos/síntese química , Isoflavonas/síntese química , Bases de Mannich/química , Piranos/síntese química , Xantenos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Humanos , Isoflavonas/farmacologia , Piranos/farmacologia , Estereoisomerismo , Xantenos/farmacologiaRESUMO
The regiospecific Mannich aminomethylation of 7-hydroxyisoflavonoids using bis(N,N-dimethylamino)methane afforded C-8 substituted N,N-dimethylaminomethyl adducts, and the regioselective aminomethylation of 5-hydroxy-7-methoxyisoflavonoids afforded predominantly the C-6 substituted N,N-dimethylaminomethyl adducts. Acetylation of these C-6 or C-8 Mannich bases with potassium acetate in acetic anhydride provided access to the corresponding acetoxymethyl derivatives that were subsequently converted to hydroxymethyl- and methoxymethyl-substituted 5-hydroxy- or 7-hydroxyisoflavonoids related to naturally occurring flavonoids. The C-8 acetoxymethyl, hydroxymethyl or methoxymethyl-substituted isoflavonoids possessed promising inhibitory potency in the low micromolar range in a prostate cancer PC-3 cell proliferation assay.