Thioether and Ether Furofuran Lignans: Semisynthesis, Reaction Mechanism, and Inhibitory Effect against α-Glucosidase and Free Radicals.

The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study, the semisynthesis of 28 furofuran lignans using samin (5) as the starting material is described. Our methodology involved the protonation of samin (5) to generate an oxocarbenium ion followed by the attack from two different nucleophiles, namely, thiols (RSH) and alcohols (ROH). The highly diastereoselective thioether and ether furofuran lignans were obtained, and their configurations were confirmed by 2D NMR and X-ray crystallography. The mechanism underlying the reaction was studied by monitoring 1H NMR and computational calculations, that is, the diastereomeric α- and ß-products were equally formed through the SN1-like mechanism, while the ß-product was gradually transformed via an SN2-like mechanism to the α-congener in the late step. Upon evaluation of the inhibitory effect of the synthesized lignans against α-glucosidases and free radicals, the lignans 7f and 7o of the phenolic hydroxyl group were the most potent inhibitors. Additionally, the mechanisms underlying the α-glucosidase inhibition of 7f and 7o were verified to be of a mixed manner and noncompetitive inhibition, respectively. The results indicated that both 7f and 7o possessed promising antidiabetic activity, while simultaneously inhibiting α-glucosidases and free radicals.

Synthesis of furofuran lignans as antidiabetic agents simultaneously achieved by inhibiting α-glucosidase and free radical.

Furofuran lignans such as sesamin have been recognized as promising antidiabetic agents as they possess curative as well as preventive effects toward diabetes complications. However, to date the structure-activity relationship has not been investigated due to the lack of a practical synthetic route capable of producing diverse furofuran lignans. Herein, we first introduced a single-step synthesis of these compounds starting from samin (4). Reaction of samin with a variety of electron-rich phenolics under acidic conditions afforded a total of 23 diverse furofuran lignans. On examination their inhibitions against α-glucosidase and free radicals, lignans having a free hydroxy group showed considerably enhanced inhibition, compared with their corresponding starter 4 and related lignans sesamin (1) and sesamolin (3). In addition, the mechanism underlying the α-glucosidase inhibition of a particular active lignan (epi -6) was verified to be mixed manner between competitive and noncompetitive inhibition.