Bioactive alkaloids from Nepalese Corydalis chaerophylla D.C. acting on the regulation of PCSK9 and LDL‐R in vitro

Four new alkaloids Chaeronepaline‐A ( 1 ), Chaeronepaline‐B ( 2 ), Chaeronepaline‐C ( 3 ), and Chaeronepaline‐D ( 4 ) were isolated from Corydalis chaerophylla D.C. collected from Nepal and their structures were elucidated by spectroscopic data, 1D, 2D NMR and mass spectrometry. The structures were established as 3,12‐ Dimethoxy‐5,6‐dihydroisoquinolino [2,1‐b] isoquinolin‐ 7‐ ium‐ 2, 9‐ diol ( 1 ), 7‐Methyl‐2,3 : 11,12‐bis(methylenedioxy)‐7,13a‐secoberbin‐13–14‐epoxide ( 2 ), 7‐ methyl‐5, 6, 7, 8‐ tetrahydro‐ 8H‐spiro‐9,14‐dihydroxy‐11,12‐methylenedioxy‐indane‐isoquinoline ( 3 ) and 7‐ methyl‐5, 6, 7, 8‐ tetrahydro‐ 8H‐spiro‐9,14‐dihydroxy‐11,12‐methylenedioxy‐indane‐isoquinoline‐N‐oxide ( 4 ). The new alkaloids were tested in human hepatoma cell line to assess their ability to modulate the expression of low‐density lipoprotein receptor (LDL−R), of proprotein convertase subtilisin/kexin 9 (PCSK9) and to affect cellular cholesterol biosynthesis with the aim to evaluate their potential hypocholesterolemic effect. Results indicated that compounds 2 and 3 upregulate the LDLR, and inhibited the cholesterol biosynthesis with compound 2 , which also reduced the secretion of PCSK9 by Huh7 cells. These in vitro data indicated a potential hypocholesterolemic effect of compound 2 that requires further in vivo validation.