Development of novel celastrol-ligustrazine hybrids as potent peroxiredoxin 1 inhibitors against lung cancer

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Disrupting oxidation-reduction balance via reactive oxygen species (ROS) modulation is a promising cancer therapy strategy.
• Inhibiting ROS clearance or enhancing ROS production offers therapeutic potential.

Purpose of the Study:

• To design and synthesize novel celastrol-ligustrazine hybrids as effective ROS promoters for cancer treatment.
• To evaluate the biological activities and therapeutic potential of these hybrid compounds, particularly their PRDX1 inhibitory effects.

Main Methods:

• Synthesis of a series of celastrol-ligustrazine hybrids.
• In vitro evaluation of PRDX1 inhibition, ROS accumulation, cancer cell proliferation, invasion, migration, and apoptosis.
• In vitro analysis of signaling pathways (AKT, ERK) and apoptosis-related proteins in A549 cells.
• In vivo antitumor efficacy and toxicity assessment.

Main Results:

• Compound 7e demonstrated superior PRDX1 inhibition (IC50 = 0.164 μM) compared to Conoidin A and celastrol.
• 7e significantly induced intracellular ROS accumulation, inhibited cancer cell proliferation, invasion, and migration, and promoted apoptosis in vitro.
• 7e suppressed AKT and ERK signaling pathways and upregulated apoptosis markers (cleaved caspase-3/8, cleaved PARP) in A549 cells.
• In vivo, 7e exhibited enhanced antitumor efficacy (TGI = 77.47%) with reduced toxicity compared to celastrol (TGI = 71.00%).

Conclusions:

• Compound 7e is a potent PRDX1 inhibitor with significant in vitro and in vivo anticancer activity.
• 7e's mechanism involves ROS promotion, apoptosis induction, and suppression of key cancer signaling pathways.
• Compound 7e represents a promising therapeutic candidate for lung cancer treatment.