Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

Abstract

A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for activity. Among them, compound 6n displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound 6n was selected for further study as an ideal liver fibrosis lead for next investigation.

IRE1α/NOX4 signaling pathway mediates ROS‐dependent activation of hepatic stellate cells in NaAsO2‐induced liver fibrosis

“…Following profibrogenic stimulus, the quiescent HSCs will differentiate into myofibroblast‐like cells with increased expression of collagen type 1 (Collagen‐1) and α‐smooth muscle actin (α‐SMA; Derynck & Zhang, 2003; Kumar et al, 2018; Ning et al, 2017). It has been demonstrated that As can cause the activation of HSCs and liver fibrosis via inflammatory responses and oxidative stress (Ghatak et al, 2011; Niu et al, 2018). Moreover, similar evidence was also found in our previous study (Wang et al, 2019), but the specific mechanisms are still scarce.…”

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

“…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].…”

Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

“…In view of the key role of COL1 in promoting hepatic fibrosis, an in vitro cell model that was based on the COL1A1 promoter was established, in which the activity of luciferase could be elevated by activators, like TGF-β1, or inhibited by candidate agents [10]. This model had been successfully applied to the screening and evaluation of anti-hepatic fibrosis drug candidates in our earlier studies [11][12][13][14]. The compound stood out in the anti-COL1A1 assay might effectively repress HF in vivo [11].…”