12N-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells

Molecules. 2019 Oct 17;24(20):3748. doi: 10.3390/molecules24203748.

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.

Keywords: COL1A1; Integrin/FAK pathway; Liver fibrosis; Matrinol; Structure−activity relationship.

MeSH terms

  • Cell Line
  • Collagen Type I / antagonists & inhibitors
  • Collagen Type I / genetics*
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Fibrosis / prevention & control
  • Focal Adhesion Kinase 1 / antagonists & inhibitors
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Integrin alphaV / genetics
  • Integrin alphaV / metabolism
  • Models, Biological
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacology*

Substances

  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Heterocyclic Compounds, 4 or More Rings
  • Integrin alphaV
  • RNA, Messenger
  • Thiazoles
  • Phosphatidylinositol 3-Kinase
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Proto-Oncogene Proteins c-akt