%0 Journal Article
%T Anti-Diabetic Activity of 2,3,6-Tribromo-4,5-Dihydroxybenzyl Derivatives from Symphyocladia latiuscula through PTP1B Downregulation and ¦Á-Glucosidase Inhibition
%J Marine Drugs | An Open Access Journal from MDPI
%D 2019
%R https://doi.org/10.3390/md17030166
%X The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and ¦Á-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and ¦Á-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol ( 1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether ( 2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) ( 3). All compounds inhibited the target enzymes by 50% at concentrations below 10 ¦ÌM. The activity of 1 and 2 was comparable to ursolic acid (IC 50; 8.66 ¡À 0.82 ¦ÌM); however, 3 was more potent (IC 50; 5.29 ¡À 0.08 ¦ÌM) against PTP1B. Interestingly, the activity of 1¨C 3 against ¦Á-glucosidase was 30¨C110 times higher than acarbose (IC 50; 212.66 ¡À 0.35 ¦ÌM). Again, 3 was the most potent ¦Á-glucosidase inhibitor (IC 50; 1.92 ¡À 0.02 ¦ÌM). Similarly, 1¨C 3 showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7¨COH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from S. latiuscula, especially highly brominated 3, are inhibitors of PTP1B and ¦Á-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs. View Full-Tex
%U https://www.mdpi.com/1660-3397/17/3/166