Synthesis and antidiabetic activity of furofuran lignans containing multiphenolic groups

Abstract

Synthesis of furofuran lignans containing multiphenolic groups (6-12) was carried out. The starting material samin (5) was obtained by acid hydrolysis of sesamin (2), which was isolated from sesame seed oil. A series of target lignans were synthesized from samin (5) and a varity of phenolics through Friedel-Crafts reaction, yielding desired products (6). To increase number of hydroxy moieties on the synthesized lignans, oxidative reaction using lead (IV) tetraacetate was performed. Removal of methylenedioxy of furofuran lignans containing a phenolic moiety produced unexpected products which contains para-quinone together with ortho-dihydroxy moieties on furofuran core structures (8-9). Consequently, to avoid oxidation of hydroxy groups, protection reaction was operated before oxidative cleavage was applied. Specially, tetra-n-butylammonium fluoride (TBAF) was successfully applied to remove protecting groups and methylenedioxy moiety in one step to obtain the desired products (11-12). The synthesized furofuran lignans (6-12) were further evaluated for antidiabetic activity through a-glucosidase inhibition. This experiment indicated that the number of free phenolic groups plays important role in a-glucosidase inhibition. The most potent inhibitor is beta-12 (IC50 25.7, 12.9 and 5.3 µM for maltase, sucrase and baker’s yeast, respectively) which contains acetoxy and four hydroxy units on a furofuran lignan. Moreover, conformation at C-2 of furofuran core also has effect on a-glucosidase inhibition, in which b-products enhanced inhibition higher than a-products. Furthermore, ortho-dihydroxy also play important role to increase a-glucosidase inhibition. For kinetic study represented that furofuran lignans inhibited the enzymes by non-competitive and mixed inhibition. As mixed inhibition, furofuran lignans were predominantly inhibited by pathway of enzyme-inhibitor (EI) complex.