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Structure-Activity Relationship of Aloperine Derivatives as New Anti-Liver Fibrogenic Agents.

ABSTRACT: Twenty-seven novel 12N-substituted aloperine derivatives were synthesized and investigated for their inhibitory effects on collagen ?1 (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 ?M. 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 ?1 (TGF-?1) and smooth muscle actin (?-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.

SUBMITTER: Wang K 

PROVIDER: S-EPMC7663597 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Structure-Activity Relationship of Aloperine Derivatives as New Anti-Liver Fibrogenic Agents.

Wang Kun K   Guo Zhihao Z   Bao Yunyang Y   Pang Yudong Y   Li Yinghong Y   He Hongwei H   Song Danqing D  

Molecules (Basel, Switzerland) 20201027 21

Twenty-seven novel 12<i>N</i>-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 (<b>1</b>) as the hit. A structure-activity relationship (SAR) study disclosed that the introduction of suitable substituents on the 12<i>N</i> atom might enhance the activity. Compound <b>4p</b> exhibited a good promise on down-regulating COL1A1 expression with the IC<sub>50</sub  ...[more]

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