Synthesis and pharmacological evaluation of brominated derivatives of natural product celastrol for treatment of hepatic fibrosis.

Effective therapeutic agents against hepatic fibrosis remain scarce. Natural product Celastrol has demonstrated promising anti-hepatic fibrosis activity. However, further clinical development is impaired by its toxicity. We performed a bromination modification at the C-ring, an unexplored moiety of Celastrol, leading to a series of brominated derivatives. Among them, derivative 5 effectively suppressed various stimulus-induced activation of NLRP3 inflammasome to block the activation of HSCs, thus reducing the collagen deposition. Meanwhile, 5 was identified as a covalent PRDX1 inhibitor with high isoform selectivity, which accelerated ROS accumulation to induce apoptosis of the activated HSCs. Derivative 5 at a dose of 20 mg/kg exhibited superior safety profile with no significant weight loss or hepatotoxicity. At 1 mg/kg, it significantly ameliorates CCl4-induced hepatic damage and fibrosis in mice. Taken together, our work provided a novel brominated derivative of Celastrol as promising lead compound against hepatic fibrosis.