Abstract
Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure–activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro-d-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.
Highlights
Impaired glucose tolerance increases the risk of vascular events such as atherosclerotic coronary artery disease [1,2]
We focused on the evaluation of the influence of the hemiacetal hydroxyl and the HHDP functionalities against the α-glucosidase inhibitory activity
We synthesized 21 carbohydrate-based phenolic analogs including a series of compounds containing all possible combinations of galloylation on 1,5-AG
Summary
Impaired glucose tolerance increases the risk of vascular events such as atherosclerotic coronary artery disease [1,2]. Postprandial hyperglycemia is a serious risk factor for cardiovascular diseases and is believed to be the cause of oxidative stress that leads to vascular events [3,4,5,6,7]. Α-glucosidase inhibitors such as acarbose, miglitol, and voglibose, belong to the class of antidiabetic drugs used for improving postprandial hyperglycemia [8,9,10,11]. Natural products and their derivatives constitute more than half of the drugs in the clinic [12,13,14,15]. Finding inspiration in nature to develop more efficient and effective medicines has attracted significant interest
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