Fused-ring α-pyrones from intramolecular C–H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation

Lipids-lowering is considered as the most effective approach to decrease the risk of Atherosclerotic cardiovas-cular disease (ASCVD), of which atherosclerosis is the most common cause. Natural products containing a unique type of alpha-pyrone was reported to suppress atherosclerosis in which alpha-pyrone might be considered as an important pharmacore. In this study, an efficient one-pot intramolecular C-H activation strategy was applied to the syn-thesis of potentially bioactive alpha-pyrone derivatives. As the result, three different scaffolds were quickly and conveniently generated, including thiophenes, pyrrole and indole derivatives. Among of them, eight alpha-pyrone derivatives showed potential effects to promote the uptake of LDL in HepG2 cells. Active unique alpha-pyrones compounds exhibiting potent in vitro and in vivo lipids-lowering effects, and a novel mechanism associated with the regulation of LXR-IDOL-LDLR axis, the new pathway targeted pharmacologically to control plasma choles-terol levels, were disclosed firstly in this study.