RESUMEN
Calystegines are potent glycosidase inhibitors with therapeutic potential and are constituents of food and feed with potential toxic effects. This study aims to target calystegines and other nitrogenous substances in food plants. Hydroalcoholic extracts from Solanum tuberosum, Ipomoea batatas, S. lycocarpum, and fruit from S. lycopersicum, S. aethiopicum, S. paniculatum, S. crinitum, and S. acanthodes were analyzed by liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) using an acidic HILIC column. The dereplication approach included data processing using MZMine2, FBMN-GNPS, and structure elucidation and interpretation of the organized data. The calystegines A3, A5, B2, and C1 were identified, and several potential new calystegine analogues: three may correspond to new calystegines of the A-group, one glycosyl derivative of calystegine A3, and two glycosyl derivatives of the B-group. These findings help to direct the search for new calystegines. In addition, the dereplication approach enabled the annotation of 22 other nitrogen compounds.
Asunto(s)
Solanum , Plantas Comestibles , Espectrometría de Masas en Tándem , Frutas , BrasilRESUMEN
Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.
Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Glicósido Hidrolasas/antagonistas & inhibidores , Glicosiltransferasas/antagonistas & inhibidores , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Compuestos Heterocíclicos con 1 Anillo/química , Humanos , Iminopiranosas/química , Iminopiranosas/uso terapéutico , Inflamación , Estructura Molecular , Mutación , Eliminación de Secuencia , Tartratos/química , Tartratos/uso terapéuticoRESUMEN
A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 ß-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N'-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/enzimología , Glucosilceramidasa/antagonistas & inhibidores , Glucosilceramidasa/genética , Iminoazúcares/uso terapéutico , Chaperonas Moleculares/uso terapéutico , 1-Desoxinojirimicina/uso terapéutico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Enfermedad de Gaucher/genética , Glucosamina/análogos & derivados , Glucosamina/uso terapéutico , Humanos , MutaciónRESUMEN
The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two ß-glucosidase (almond) inhibitors (14b,f) in the low µM range. The additional biological analysis of 14b,f towards ß-glucocerebrosidase (human lysosomal ß-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards ß-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver ß-glucosidase as neutral hydrolase. In contrast to what was observed for ß-glucosidase inhibition, the coffee bean α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Pirrolidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Triazoles/farmacología , alfa-Galactosidasa/antagonistas & inhibidores , beta-Glucosidasa/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , alfa-Galactosidasa/metabolismo , beta-Glucosidasa/metabolismoRESUMEN
A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon their in vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 µM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 µM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 µM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 µM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 µM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin.