RESUMEN
Due to the side effects of synthetic drugs, the therapeutic potential of natural products for Alzheimer's disease (AD) has gained interest. Morinda officinalis has demonstrated inhibitory effects on geriatric diseases, such as bone loss and osteoporosis. However, although AD is a geriatric disease, M. officinalis has not been evaluated in an AD bioassay. Therefore, M. officinalis extracts and fractions were tested for AD-related activity, including inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), and advanced glycation end-product (AGE) formation. A bioassay-guided approach led to isolation of 10 active compounds, eight anthraquinones (1-8), one coumarin (9), and one phytosterol (10), from n-hexane and ethyl acetate fractions of M. officinalis. The five anthraquinones (4-8) were stronger inhibitors of AChE than were other compounds. Compounds 3 and 9 were good inhibitors of BChE, and compounds 3 and 8 were good inhibitors of BACE1. Compounds 1-5 and 7-9 were more active than the positive control in inhibiting AGE formation. In addition, we first suggested a structure-activity relationship by which anthraquinones inhibit AChE and BACE1. Our findings demonstrate the preventive and therapeutic efficacy of M. officinalis for AD and its potential use as a natural alternative medicine.
Asunto(s)
Bioensayo/métodos , Descubrimiento de Drogas , Morinda/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas/métodos , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Relación Estructura-ActividadRESUMEN
This study aimed to optimize the preparation of L-α-glycerylphosphorylcholine (l-α-GPC) via phospholipase A1 (Lecitase Ultra)-catalyzed hydrolysis of soy phosphatidylcholine (PC). The reaction was performed in n-hexane-water biphasic media in a stirred batch reactor, and modeling and optimization were conducted using response surface methodology. Optimal conditions to completely hydrolyze PC to L-α-GPC were: temperature, 50 °C; reaction time, 30 h; water content, 69 g/100 g of PC weight; and enzyme loading, 13 g/100 g of PC weight. The optimal n-hexane-to-water ratio in the medium was 5.8:1 (v/v), and 21.3g of PC was treated as the substrate in 100 mL of the medium. L-α-GPC with purity 99.3 g/100 g was obtained from the reaction products after diethyl ether extraction and silica column chromatography. These findings suggest that the use of n-hexane-water media increases the productivity of l-α-GPC compared to the aqueous media used in enzymatic reaction systems in other published studies.
Asunto(s)
Glicerilfosforilcolina/química , Fosfatidilcolinas/química , Fosfolipasas A1/química , Alimentos de Soja/análisis , Catálisis , HidrólisisRESUMEN
Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.