Anti-Diabetic Activity of 2,3,6-Tribromo-4,5-Dihydroxybenzyl Derivatives from Symphyocladia latiuscula through PTP1B Downregulation and ?-Glucosidase Inhibition.

ABSTRACT: 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 ?-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 ?-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 ?M. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 ?M); however, 3 was more potent (IC50; 5.29 ± 0.08 ?M) against PTP1B. Interestingly, the activity of 1?3 against ?-glucosidase was 30?110 times higher than acarbose (IC50; 212.66 ± 0.35 ?M). Again, 3 was the most potent ?-glucosidase inhibitor (IC50; 1.92 ± 0.02 ?M). Similarly, 1?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?OH 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 ?-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.

SUBMITTER: Paudel P 

PROVIDER: S-EPMC6471218 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature