Twenty-seven novel 12N-substituted aloperine derivatives were synthesized and investigated for their inhibitory effects on collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells, taking aloperine (1) as the hit. A structure-activity relationship (SAR) study disclosed that the introduction of suitable substituents on the 12N atom might enhance the activity. Compound 4p exhibited a good promise on down-regulating COL1A1 expression with the IC50 value of 16.5 μM. Its inhibitory activity against COL1A1 was further confirmed on both mRNA and protein levels. Meanwhile, it effectively inhibited the expression of other fibrogenic proteins, such as transforming growth factor β1 (TGF-β1) and smooth muscle actin (α-SMA). It also exhibited good in vivo safety profile with the oral LD50 value of 400 mg kg-1 in mice. The results initiated the anti-liver fibrogenic study of aloperine derivatives, and the key compound 4p was selected as a novel lead for further investigation against liver fibrogenesis.
Keywords: COL1A1; aloperine; anti-liver fibrogenesis; structure−activity relationship.