α-GLUCOSIDASE INHIBITORS FROM N-SUBSTITUTED AMINOCYCLITOL DERIVATIVES AND TOTAL SYNTHESIS OF CJ-16,264

Abstract

An efficient synthesis of α-glucosidase inhibitors; conduritol and its analogues, and N-substituted aminoquercitols, from naturally available (+)-proto-quercitol was investigated. Proper configuration of (+)-proto-quercitol perfectly set up for regioselective protection of hydroxyl group which was further functionalized into various α-glucosidase inhibitors in a straightforward manner. This synthetic method provided a concise synthesis of α-glucosidase inhibitors in a large quantity. From this investigation, over 40 new N-substituted aminoquercitols and conduritol analogues were synthesized. Among them, (+)-conduritol F was the most potent type I α-glucosidase inhibitor with an IC50 value of 86.1 µM, which is five times greater than the standard antidiabetic drug, Acarbose. On the other hand, a series of N-substituted aminoquercitols showed highly improved inhibition against rat intestinal maltase (type II α-glucosidase). Of all synthesized compounds, 5-1 and 5-9 were the most active inhibitors against rat intestinal maltase, which had potency similar to the most effective antidiabetic drug, Voglibose. Kinetic study of N-substituted aminoquercitols indicated that they retarded maltase function in a competitive manner. A molecular docking study suggested that the hydrogen bonding, from hydroxyl groups at aminoquercitol moiety and N-alkyl side chain with the key residues in the rat maltase active site, played an important role in molecular interactions. In addition, the –NH group might also form the hydrogen bond within the active site of enzyme. 3D-QSAR study emphasized structural features around N-substituted part of aminoquercitol derivatives as the α-glucosidase inhibitory activity. The resulting contour maps from the 3D-QSAR models provide a good insight into the molecular features relevant to the biological activity for this series, suggesting that the less steric and hydrophilic groups at N-position of aminoquercitol could increase activity. This is the first report on molecular docking and 3D-QSAR modeling for a series of N-substituted aminoquercitols toward the modeled rat intestinal maltase. Compounds 5-1 and 5-9 therefore represent a new class of promising compounds that can improve α-glucosidase inhibitory activity. Moreover, the diastereoselective total synthesis of antibiotic CJ-16,264 analogue (1-epi-CJ-16,264) has been completed in 18 steps from commercially available citronellal. The key steps involved an exo-selective IMDA reaction of macrolactone to furnish the cis-decalin scaffold and boron-mediated Reformatsky reaction affording the full CJ-16,264 skeleton in high yield with exquisite stereoselectivity.