Potential Therapeutics For Treating Type 2 Diabetes Mellitus

Bromophenols have been identified as potential therapeutics for treating type 2 diabetes mellitus (T2DM) due to their suspected tyrosine phosphatase 1B (PTP1B) inhibitory activity. A new series of bromophenol analogues will be synthesised and their PTP1B inhibitory activity will be tested in in vitro enzymatic assays to elucidate their mechanism of action as PTP1B inhibitors. Background and Introduction Type 2 diabetes mellitus (T2DM) is a metabolic disease that is caused by insulin resistance of the peripheral tissues and impaired insulin secretion of the pancreatic ÃŽ ² cells.1 Both conditions result in reduced glycemic control, which can lead to hyperglycemia. Despite the availability of a wide range of anti-diabetic drugs to treat T2DM,†¦show more content†¦Bromophenols have attracted much attention as potential PTP1B inhibitors due to their suspected anti-diabetic activity.4 Bromophenols occur naturally in marine organisms such as algae, mollusks and jellyfish. ( ±)-Polysiphenol (1, figure 1) is an example of a bromophenol that can be extracted from the marine algae Polisiphonia Ferulecea.5 After the Braddock group successfully achieved the first total synthesis of ( ±)-polysiphenol and the separation of its enantiomers, they collaborated with the Woscholski group to test their inhibitory activity in PTP1B enzymatic assays.6,7 Both enantiomers of polysiphenol were essentially found to be identical in PTP1B inhibitory activity. Thus polysiphenol, as single enantiomers, cannot be responsible for the observed inhibition. This implicates a chemical change of polysiphenol into a non-chiral form is likely to take place under the conditions of the assay. One possibility is the formation of a para-quinone methide species (4, figure 1), which in turn can tautomerise into an ortho-quinone methide species (5, figure 1). Thus there are various possible reactive species that might be responsible for the observed inhibition of PTP1B. The formation of quinones highlights a red flag in drug discovery due to their highly reactive nature. Quinones are Michael acceptors that are known to cause toxicity in vivo by covalently binding to nucleophilic sites on proteins and DNA.8 Consequently, quinones