Pt(IV) Complexes Incorporating CDC25A/NF-κB Dual Inhibitory 1,4-Naphthoquinone Derivatives Trigger Multimodal Cell Death in A2780 Ovarian Cancer Cells

  • J Med Chem. 2026 Jun 25;69(12):14902-14920. doi: 10.1021/acs.jmedchem.6c01327.
Yun-Hou Huang  1 ,  Yuan Liu  1 ,  Qin Hu  1 ,  Yue Huang  1 ,  Sha-Sha Luo  1 ,  Rui-Xue Liu  1 ,  Chang-Chun Wen  1 ,  Yan-Cheng Liu  1 ,  Tim Storr  2 ,  Hong Liang  1
Affiliations
  • 1. School of Chemistry and Pharmaceutical Sciences, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources (Guangxi), Guangxi Normal University, 541004 Guilin, China.
  • 2. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
PMID: 42275647 DOI: 10.1021/acs.jmedchem.6c01327
Abstract

This work presents a novel, promising, and efficient strategy to develop potential Pt(IV) prodrugs for Cancer chemotherapy while to simultaneously overcome the ″undruggability″ of CDC25A. New series of Pt(IV) complexes (Pt5-Pt13) bearing 1,4-naphthoquinone (NQ, a natural active skeleton) derivatives (c1-c3) as potential dual CDC25A/NF-κB inhibitory ligands were synthesized and characterized. Their in vitro and in vivo Anticancer activities were subsequently evaluated. Mechanistic investigations revealed that Pt6, the most potent candidate with ligand c2, effectively depleted CDC25A levels in A2780 Cancer cells through a synergistic effect mediated by DNA damage. Thus, Pt6 triggered multimodal Anticancer mechanisms, which included Reactive Oxygen Species/endoplasmic reticulum stress-mediated mitochondrial apoptotic pathway, DNA damage coupled with S-phase cell cycle arrest, and autophagy-dependent Ferroptosis. In A2780 xenograft models, Pt6 administrated with a dosage of 8 mg/kg manifested superior tumor growth inhibition than both cisplatin and "cisplatin + c2" combination, along with satisfying low toxicity.

Keywords
DNA damage; Pt(IV) complex; apoptosis; autophagy-dependent ferroptosis; cell cycle arrest; dual CDC25A/NF-κB inhibition.
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