Synthesis And PTP1B Inhibitory Activitiy Investigation Of Marine Natural Product BDB And Its Derivatives

Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes, which are crucial modulators of tyrosine phosphorylation-dependent cellular events. Among members of the PTP superfamily, PTP1B is considered one of the best validated targets for therapeutic development. Biochemical and genetic evidence indicate that PTP1B plays a key role in regulating body weight, glucose homeostasis, and energy expenditure by acting as a key negative regulator of insulin and leptin receptor mediated signaling pathways. PTP1B-deficient mice display increased insulin sensitivity and improved glycemic control, and are resistant to diet-induced obesity. These findings suggest that inhibition of PTP1B represents an effective strategy to combat metabolic syndromes such as type 2 diabetes and obesity.Bromophenols, an uncommon series of compounds with distinguished marine character were isolated from algae. These bromophenol derivatives showed diverse biological activities, such as cytotoxic, antimicrobial, antioxidant, antitumor. During our investigation of chemical and biological diversity of seaweeds distributed in the gulf of the Yellow Sea, 3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)- 1,2-benzenediol (BDB) isolated from red alga Rhodomela confervoides exhibited significant inhibition against protein tyrosine phosphatase 1B (PTP1B). We hope that more ideal PTP1B inhibitors would be synthesised through in-depth research with BDB as the lead compound.1 The synthesis of BDB. With the analysis of BDB, we designed an ideal synthetic route of BDB. From the starting materials vanillin, the synthesis of natural product BDB has been achieved (34% yields of seven steps).2 For better understanding structure-activity relationship, 50 compounds (including 27 new compounds) were designed and synthesized and the structures of these compounds were elucidated by spectroscopic methods including 1HNMR, 13CNMR, and HREIMS.3 41 compounds were screened for the PTP1B inhibition activities in vitro and 3 compounds with preferable activity were obtained. They are 4,5- bis(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxybenzene (5) (IC50=0.67μg/mL), 3-bromo-4,5-bis(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxybenzene (6) (IC50=2.58μg/mL), 2,3-dibromo-1-(2-bromo-6-(2-bromo-4,5-dimethoxybenzyl) -3,4-dimethoxybenzyl)-4,5-dimethoxybenzene (41) (IC50=1.01μg/mL).