2. Academic Validation
  3. Boosting Energy Deprivation via Synchronous Interventions of Oxidative Phosphorylation and Glycolysis for Cancer Therapy with 1,8-Naphthyridine-Piperazine-Dithiocarbamate Ruthenium(II) Polypyridyl Complexes

Boosting Energy Deprivation via Synchronous Interventions of Oxidative Phosphorylation and Glycolysis for Cancer Therapy with 1,8-Naphthyridine-Piperazine-Dithiocarbamate Ruthenium(II) Polypyridyl Complexes

  • J Med Chem. 2025 May 22;68(10):10203-10215. doi: 10.1021/acs.jmedchem.5c00384.
Huiling Wang 1,  Lei Chen 1,  Zhichen Mao 1,  Shuangqiang Liu 1,  Rizhen Huang 1,  Ruijie He 2,  Ye Zhang 1,  Jianhua Wei 1 3
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199 Guangxi, China.
  • 2 Guangxi Zhuang Autonomous Region and Chinese Academy of Sciences, Guangxi Key Laboratory of Plant Functional Phytochemicals and Sustainable Utilization, Guangxi Institute of Botany, Guilin 541006, China.
  • 3 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001 Guangxi, China.
PMID: 40353767 DOI: 10.1021/acs.jmedchem.5c00384
Abstract

Bioenergetic therapy targeting mitochondrial bioenergy is a promising therapeutic strategy for Cancer. However, its clinical efficacy is limited by the metabolic adaptability of tumor cells, as they can switch between glycolytic and Oxidative Phosphorylation metabolic phenotypes to maintain energy homeostasis. In this study, we discovered 1,8-naphthyridine-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes (RuL1) that enhanced energy deprivation by inhibiting the activity of mitochondrial complex I and III, thereby disrupting Oxidative Phosphorylation. Simultaneously, RuL1 inhibits glycolysis while unexpectedly activating antitumor immunity. This dual metabolic-immunological targeting resulted in enhanced Anticancer activity against MGC-803 cells. To the best of our knowledge, RuL1 is the first ruthenium polypyridyl complex reported to achieve high Anticancer activity through dual metabolic inhibition.

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