Abstract
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.
Highlights
Liver fibrosis, as a key pathogenic factor in chronic liver disease progression, is a consequence of chronic damage associated with alcoholic or non-alcoholic fatty liver disease, hepatitis, metabolic or genetic diseases [1,2]
Active myofibroblast-like cells are characterized by increased migration, α-smooth muscle actin (α-SMA) expression, and robust collagen production, wherein type I collagen (COL1) constitutes the main source of extracellular matrix (ECM) in clinical and experimental liver fibrosis [11,12]
12N-carbamoylmethyl aloperine derivatives 4a–p were obtained by alkylation of 1 with the key intermediates 3a–p, which were synthesized via acylation of bromoacetyl bromide with substituted amines 2a–p under alkaline conditions [15]
Summary
As a key pathogenic factor in chronic liver disease progression, is a consequence of chronic damage associated with alcoholic or non-alcoholic fatty liver disease, hepatitis, metabolic or genetic diseases [1,2]. Hepatic fibrosis is characterized by the dysregulated deposition of extracellular matrix (ECM), complexed with progressive destruction of normal liver tissue [2]. Active myofibroblast-like cells are characterized by increased migration, α-smooth muscle actin (α-SMA) expression, and robust collagen production, wherein type I collagen (COL1) constitutes the main source of extracellular matrix (ECM) in clinical and experimental liver fibrosis [11,12]. Taking COL1A1 promotor as the biomarker, a luciferase screening cell model based on the elevation effect of TGF-β1 upon the expression of COL1A1 promoter was established earlier in our group [13], and successfully applied to the screening and evaluation of anti-hepatic fibrosis drug candidates [14,15,16]. The in vivo pharmacodynamics study confirmed that compounds down-regulating the transcription of COL1A1 gene could effectively reverse liver fibrosis in vivo [15]
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