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

Seaweed Phenolics: From Extraction to Applications

“…In addition, 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether, extracted from S. latiuscula, act as multitarget ligands promoting neuroprotection [161].…”

“…Some of the identified seaweed bromophenols can be included in schizophrenia and Parkinson's disease therapies [161], because they can be used as a multitarget ligand to neurosensors. Furthermore, phlorotannins have neuroprotection action and may be the key to the treatment of neurodegenerative diseases [31].…”

“…Bromophenols present anti-diabetic effects [33,161] that could be used in the research and development of a novel class of anti-diabetic drugs or in supplements and functional food products.…”

Progress of Bromophenols in Marine Algae from 2011 to 2020: Structure, Bioactivities, and Applications

“…For example, BP 2.1 (also 6.1 and 7.1.1 ), BP 2.2 (also 6.2 ), and BP 2.3 (also 6.3 , 7.1.2 , 7.3.5 , and Scheme 2 ), isolated from the marine alga Symphyocladia latiuscula , showed antidiabetic potential by inhibiting PTP1B, and these compounds also exhibited inhibitory effects on α-glucosidase enzymes, enhancing insulin sensitivity and glucose uptake [ 64 ]. In silico molecular docking simulations also revealed the importance of the 7–OH group for H-bond formation and bromine/phenyl ring number for halogen bond interactions with the enzymes [ 64 ] (see Section 3 ). Compound 2.4 ( Scheme 2 ), from the red alga Rhodomela confervoides , represents a potential candidate for further development as an antidiabetic agent.…”

“…Docking of BP 2.1 (also 6.1 and 7.1.1 ), BP 2.2 (also 6.2 ), and BP 2.3 (also 6.3 , 7.1.2 , and 7.3.5 ) has also been done with the PTP1B enzyme. For 2.1 , the bromine atoms were involved in interactions with Thr263, Val184, Gln266, Gly183, Arg221, Phe1823, Lys116, and Trp176 [ 64 ]. An inspection of the graphics revealed major interactions to a side-chain nitrogen of Arg221 and to the OH group of Thr263, whereas the remaining interactions are to CH bonds.…”