2. Academic Validation
  3. Development of novel celastrol-ligustrazine hybrids as potent peroxiredoxin 1 inhibitors against lung cancer

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

  • Eur J Med Chem. 2023 Nov 5;259:115656. doi: 10.1016/j.ejmech.2023.115656.
Ying Bai 1,  Chao Liang 1,  Jiawei Zhou 1,  Yafeng Liu 1,  Fengxuan Wang 2,  Jian Gao 2,  Jing Wu 3,  Dong Hu 4
Affiliations

Affiliations

  • 1 School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, 232001, China.
  • 2 School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China.
  • 3 School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, 232001, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institute, Huainan, 232001, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Safety and Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, 232001, China.
  • 4 School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, 232001, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institute, Huainan, 232001, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Safety and Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, 232001, China. Electronic address: [email protected].
PMID: 37499289 DOI: 10.1016/j.ejmech.2023.115656
Abstract

The disruption of oxidation-reduction equilibrium through inhibiting Reactive Oxygen Species (ROS) clearance or enhancing ROS production has emerged as a novel and promising strategy for Cancer therapy. Herein, a series of celastrol-ligustrazine hybrids were designed and synthesized as effective ROS promoters, and their biological activities were further evaluated. Among them, compound 7e stood out as the most potent peroxiredoxin 1 (PRDX1) inhibitor (IC50 = 0.164 μM), which was significant super to the recognized PRDX1 inhibitor Conoidin A (IC50 = 14.80 μM) and the control compound celastrol (IC50 = 1.622 μM). Furthermore, 7e dramatically promoted intracellular ROS accumulation, and inhibited the proliferation, invasion and migration of Cancer cells besides inducing Apoptosis in vitro. Additionally, 7e suppressed the key signaling pathways (Akt and ERK) and promoted the expression of apoptosis-related proteins (cleaved Caspase-3/8 and cleaved PARP) in A549 cells, which resulted in the prevention of tumor progression. Most importantly, compound 7e (TGI = 77.47%) showed more considerable in vivo antitumor efficacy and less toxicity than celastrol (TGI = 71.00%). Overall, this work indicates 7e as the most potential PRDX1 inhibitor and may be a promising candidate for the therapy of lung Cancer.

Keywords

Celastrol-ligustrazine hybrids; Lung cancer; PRDX1 inhibitor; Reactive oxygen species.

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