Synthesis and structure-activity relationship study of antidiabetic penta-O-galloyl-D-glucopyranose and its analogues

摘要: The rapid increase of obesity-associated diabetes has created urgent demands for more effective antidiabetic therapies and pharmaceuticals that are able to address the problems hyperglycemia weight gain simultaneously. Our previous studies indicated alpha- beta-anomers penta-O-galloyl-D-glucopyranose (PGG), 2 3, act as insulin mimetics bind activate receptor, stimulate glucose transport in adipocytes, reduce blood levels diabetic obese animals. In addition, they inhibit differentiation preadipocytes into adipocytes. These activities suggest 3 may without increasing adiposity. To investigate structure-activity relationship four series novel compounds were prepared their stimulatory measured using a radioactive uptake bioassay. assay results indicate both galloyl groups critical activity 3. It appears core provides an optimal scaffold present with correct spatial orientation induce activity. Moreover, linked 1, 2, 4 positions essential, while group connected 6 position is unnecessary induction discovery two related compounds, 6-deoxytetra-O-galloyl-alpha-D-glucopyranose (43) tetra-O-galloyl-alpha-D-xylopyranose (59), also possess suggests be further modified around modulate enhance its efficacy. test this hypothesis, we developed new synthetic method allows stereoselective preparation derivatives on C-6. We found 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-alpha-D-glucopyranose (80) exhibits significantly higher than 2. Its comparable insulin.