Twenty-seven novel 12-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 () as the hit. A structure-activity relationship (SAR) study disclosed that the introduction of suitable substituents on the 12 atom might enhance the activity. Compound exhibited a good promise on down-regulating COL1A1 expression with the IC 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 LD value of 400 mg kg in mice. The results initiated the anti-liver fibrogenic study of aloperine derivatives, and the key compound was selected as a novel lead for further investigation against liver fibrogenesis.
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