Development and structure–activity relationships of tanshinones as selective 11 β -hydroxysteroid dehydrogenase 1 inhibitors

11 β -Hydroxysteroid dehydrogenase 1 (11 β -HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11 β -HSD1 inhibitors. To improve the druggability and explore the structure–activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11 β -HSD1 inhibitory activity and good selectivity over 11 β -HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11 β -HSD1. Remarkably, compounds 1 , 17 and 30 significantly inhibited 11 β -HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11 β -HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones. Graphic Abstract