Synthesis and Biological Evaluation of Decursinol Derivatives as FoxO-1 Inhibitors in HepG2 Cells

Abstract

Diabetes mellitus type 2 is caused by insulin resistance, often associated with increased hepatic gluconeogenesis. Forkhead box O-1 (FoxO-1) is known as a major transcription factor regulating hepatic gluconeogenesis, and the increased FoxO-1 expression and activity are mainly observed in type 2 diabetic patients. To discover new FoxO-1 inhibitors, the compounds were newly synthesized from decursinol, which is a molecule isolated from the Angelica gigas and proved to be safe. The compounds were evaluated for in vitro FoxO-1 inhibitory activity using FoxO-1 reporter assay in HepG2 cells. Among these, the compounds 2b and 2c exhibited FoxO-1 inhibitory activity with IC50 values of 98.9 and 123.7 μM, respectively. Moreover, the blood glucose level reduction efficacy of synthesized compound 2b was found similar to that of glimepiride, a commercially available antidiabetic drug and used as a reference (21.6 vs. 21.4%), in alloxan-induced type 2 diabetes rats. These findings suggest that, the compound 2b has moderate inhibitory activity on FoxO-1 and possibly resulting in the amelioration of diabetic hyperglycemia.