Benzofuran Derivatives Inhibit 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Rat Adipose Tissue

Abstract

Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and ( )-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corti-

Resveratrol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose microsomes

“…In addition, these data showed that resveratrol does not inhibit G6PT, which is located in the membrane of the endoplasmic reticulum and supplies G6P to the lumen (Chou et al 2002). Further, these results were consistent with features of previous studies, indicating that no inhibition of H6PD by E 2 and 2-arylbenzofuran derivatives was observed (Tagawa et al 2009, Kiyonaga et al 2012. These characteristic properties might also be because of the typical structure of the spatial configuration of the two hydroxyl groups as observed in resveratrol, E 2 , or 2-arylbenzofuran derivatives.…”

“…1C) and 2-(4-hydroxyphenyl)-6-benzofuranol (Fig. 1D), having a distance of w12 Å between the two hydroxyl groups in their molecules, inhibited 11b-HSD1 activity without 11b-HSD2 inhibition (Kiyonaga et al 2012). Therefore, two hydroxyl groups at the C-4 0 and C-3 or C-5 positions with the same distance (w12 Å ) in resveratrol may be crucial for the selective inhibition of 11b-HSD1.…”

“…These hydroxyl groups at the C-3 and C-17 positions of E 2 were indispensable for the inhibitory effect of 11b-HSD1 activity, which was revealed by the structureactivity relationship of those groups. Further, the distance between these two hydroxyl groups of E 2 was 12.12 Å (Kiyonaga et al 2012;Fig. 1B), whereas resveratrol (3, 4 0 , 5-trihydroxystilbene) bears three hydroxyl groups.…”

“…1C and D), the distances of which were w12 Å (similar to E 2 ), inhibited 11b-HSD1 activity in a non-competitive manner in rodent adipocytes (Kiyonaga et al 2012). These findings prompted us to examine whether the compound bearing a structural resemblance to the spatial configuration of the two hydroxyl groups in E 2 inhibits 11b-HSD1 activity.…”

Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11β-hydroxysteroid dehydrogenase type 1

“…6.1, and found to be about 12-13 Å (13.48 Å, Fig. 1A), is approximately the same as the corresponding distance in 17b-estradiol (12.12 Å) [22]. These findings prompted us to examine whether genistein has inhibitory effects on 11b-HSD1 and H6PD activities.…”