ABSTRACT
A series of new cytisine derivatives with a unique endocyclic scaffold were synthesized and evaluated for their inhibitory effect on collagen α1 (I) (COL1A1) promotor in human LX2 cells, taking cytisine as the lead. Structure-activity relationship (SAR) revealed that introducing a 12N-benzyl substitution might significantly enhance the activity. Compound 5f exhibited a promising inhibitory potency against COL1A1 with an IC50 value of 12.8⯵M in human LX2 cells, and an inspiring inhibition activity against COL1A1 on both mRNA and protein levels. It also effectively inhibited the expression of α smooth muscle actin (α-SMA), connective tissue growth factor (CTGA), matrix metalloprotein 2 (MMP-2), and transforming growth factor ß1 (TGFß1), indicating an extensive inhibitory effect against fibrogenetic proteins. In addition, compound 5f displayed reasonable PK and safety profiles. The primary mechanism study indicated that it might repress the hepatic fibrogenesis via PI3K/Akt/Smad signaling pathway. The results provided powerful information for further structure optimization, and compound 5f was selected as a novel anti-liver fibrosis agent for further investigation.