RESUMEN
The fragments, 3,4-(methylenedioxy)cinnamic acid amide and dithiocarbamates, have received increasing attention because of their multiple pharmacological activities in recent years, especially in anti-tumor. We synthesized 17 novel 3,4-(methylenedioxy)cinnamic acid amide-dithiocarbamate derivatives based on the principle of pharmacophore assembly and discovered that compound 4a7 displayed the most potent antiproliferative activity against HeLa cells with IC50 value of 1.01â µM. Further mechanistic studies revealed that 4a7 triggered apoptosis in HeLa cells via activating mitochondria-mediated intrinsic pathways and effectively inhibited colony formation. Also, 4a7 had the ability to arrest cell cycle in the G2/M phase as well as to inhibit the migration in HeLa cells. More importantly, acute toxicity experiments showed that 4a7 had good safety inâ vivo. All the results suggested that compound 4a7 might serve as a promising lead compound that merited further attention in future anti-tumor drug discovery.
Asunto(s)
Amidas , Antineoplásicos , Amidas/farmacología , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Cinamatos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Relación Estructura-ActividadRESUMEN
A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.
Asunto(s)
Amidas/farmacología , Inhibidores de la Colinesterasa/farmacología , Cinamatos/farmacología , Ésteres/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Acetilcolinesterasa/metabolismo , Amidas/síntesis química , Amidas/química , Animales , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Cinamatos/síntesis química , Cinamatos/química , Relación Dosis-Respuesta a Droga , Ésteres/síntesis química , Ésteres/química , Caballos , Humanos , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Relación Estructura-ActividadRESUMEN
The α-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of α-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1-3) were ascertained to be active components against α-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of α-glucosidase (IC50 = 0.42 µM). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for α-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both Km and Vmax, and Kik/Kiv ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An α, ß-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for α-glucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to π-π interaction as well as hydrogen bond interaction between enzyme and inhibitors.