Abstract
Twenty new 12N-substituted matrinol derivatives were synthesized and evaluated for their inhibitory effects on collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure-activity relationship (SAR) revealed that introducing a 12N-benzeneaminoacylmethyl substitution might significantly enhance the activity. Compound 8a exhibited the highest inhibitory potency against COL1A1, and its inhibition activity against COL1A1 was further confirmed on both the mRNA and protein levels. It also effectively inhibited the expression of α smooth muscle actin (α-SMA), fibronectin and transforming growth factor β1 (TGFβ1), indicating an extensive inhibitory effect on the expression of fibrogenic genes. The primary mechanism study indicated that it might take action via the Integrin/FAK/PI3K/Akt signaling pathway. The results provided powerful information for further structure optimization, and compound 8a was selected as a novel anti-fibrogenic lead for further investigation.
Highlights
Liver fibrosis refers to a reversible pathological process of an excessive precipitation of the hepatic diffuse extracellular matrix (ECM) in the liver which is caused by the abnormal proliferation of connective tissue
The structure-activity relationship (SAR) indicated that the introduction of benzeneaminoacylmethyl motif on the 12N atom was favorable for the activity
Its inhibition activity against COL1A1 was further confirmed on both the mRNA and protein levels. It effectively inhibited the expression of a series of fibrogenic proteins, such as α smooth muscle actin (α-SMA), fibronectin and TGFβ, indicating a promise against liver fibrogenesis
Summary
Liver fibrosis refers to a reversible pathological process of an excessive precipitation of the hepatic diffuse extracellular matrix (ECM) in the liver which is caused by the abnormal proliferation of connective tissue. It seriously affects the function of liver, and is an inevitable stage for the development of chronic liver disease into fatal cirrhosis [1,2,3]. Liver fibrosis affects a large population, and more seriously, the morbidity crowd displays a younger trend annually [4]. There is still a great demand to develop new anti-liver fibrosis candidates The treatment for liver fibrosis has been quite limited up to now [5].
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