# Design, Synthesis, and Anti-Hepatic Fibrosis Evaluation of Cordycepin Derivatives

## TL;DR

This study designs and tests cordycepin derivatives to find new anti-liver fibrosis compounds that inhibit cell activation and improve liver health.

## Contribution

The study introduces cordycepin derivative 3a, which shows enhanced anti-fibrotic activity and activates the AMPK signaling pathway.

## Key findings

- Compound 3a dose-dependently downregulates α-SMA and collagen-I at mRNA and protein levels.
- Compound 3a inhibits LX-2 cell migration and shows improved metabolic stability in liver microsomes.
- Compound 3a activates the AMPK signaling pathway, suggesting a potential mechanism for its anti-fibrotic effect.

## Abstract

Activation of hepatic stellate cells (HSCs) featuring upregulated expression of α-smooth muscle actin (α-SMA) is recognized as a key driver for hepatic fibrosis, which provides a promising strategy for seeking anti-liver fibrogenic agents via suppressing the activation event. In this study, we designed and synthesized twenty-eight cordycepin derivatives through structural modifications at the C2 position and the C6-NH2 group of the purine moiety. These compounds were screened for their inhibitory effects on HSC activation by detecting the mRNA expression of α-SMA using quantitative real-time polymerase chain reaction (qPCR) in the LX-2 cell model. Most compounds displayed inhibitory activity comparable to cordycepin, with compound 3a bearing a C2-chloro and a N6-methyl-N6-(2-chlorobenzyl) substituent, demonstrating enhanced in vitro anti-fibrotic effect. This compound was able to dose-dependently downregulate α-SMA and collagen-I at both mRNA and protein levels, inhibited LX-2 cell migration, and exhibited improved metabolic stability in liver microsomes. The Western blotting result also indicated that 3a could activate the AMPK signaling pathway. Overall, these results suggest 3a may serve as a lead compound for further investigation.