Synthesis and characterization of β-glucogallin as an aldose reductase inhibitor from Emblica officinalis

As the prevalence of diabetes mellitus continues to grow at epidemic proportions, the development of novel therapeutics to prevent the progression of diabetic retinopathy and cataract is paramount to eliminating secondary blindness in diabetic patients. Aldose reductase (AKR1B1) has been implicated in the progression of diabetic complications through the catalytic reduction of glucose to sorbitol. However, clinical trials of aldose reductase inhibitors have failed, most prominently due to toxicity as a result of nonspecific inhibition of other members of the aldo-keto reductase (AKR) superfamily. We recently identified the polyphenolic compound 1-O-galloyl-β-D-glucose (β-glucogallin) as the major active component of aqueous extracts from Emblica officinalis fruits, which have been shown to effectively treat cataracts in a diabetic rat model. Fruits of E. officinalis have been consumed for millennia in traditional Ayurvedic preparations. Herein we present the stereospecific synthesis of β-glucogallin from gallic acid, as well as its characterization as a potent (IC₅₀=17µM) as well as a specific inhibitor of AKR1B1. Molecular modeling demonstrates how β-glucogallin is able to bind both active site and specificity pocket residues of AKR1B1 and is utilized to drive rational drug design using the polyphenolic glycoside scaffold. This work supports the continued use of natural products such as β-glucogallin as therapeutic leads to treat diabetic complications.