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 α-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 α-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 μM. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 μM); however, 3 was more potent (IC50; 5.29 ± 0.08 μM) against PTP1B. Interestingly, the activity of 1–3 against α-glucosidase was 30–110 times higher than acarbose (IC50; 212.66 ± 0.35 μM). Again, 3 was the most potent α-glucosidase inhibitor (IC50; 1.92 ± 0.02 μM). 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 α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.
Highlights
Diabetes is a group of metabolic diseases characterized by high blood sugar levels
Enzyme inhibition levels are expressed as mean IC50 values with standard deviation
Structural insights into the Protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase enzymes inhibition revealed the importance of bromine and phenolic group number
Summary
Diabetes is a group of metabolic diseases characterized by high blood sugar levels. It can lead to blurred vision, cardiovascular diseases, kidney and/or other organ damage and dysfunction, and even depression [1]. Diabetes is caused by a failure of the pancreas to produce insulin (type I diabetes) or by insulin resistance (cells do not respond to insulin; type II diabetes). Type II diabetes mellitus (T2DM) accounts for more than 90% of total diabetes cases [2]. Protein tyrosine phosphatase 1B (PTP1B) downregulates insulin signaling by catalyzing the dephosphorylation of. Mar. Drugs 2019, 17, 166; doi:10.3390/md17030166 www.mdpi.com/journal/marinedrugs
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