2. Academic Validation
  3. Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance

Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance

  • J Med Chem. 2025 Mar 13;68(5):5597-5615. doi: 10.1021/acs.jmedchem.4c02840.
Meng Wang 1 2,  Guimei Li 2,  Nan Xu 1,  Lang Wang 1,  Jinyuan Cai 1,  Rizhen Huang 3,  Yong Yang 1,  Guiping Chen 1,  Zhikun Liu 1,  Ye Zhang 3,  Hengshan Wang 2,  Xiaochao Huang 1 2
Affiliations

Affiliations

  • 1 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China.
  • 2 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center For Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
  • 3 Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
PMID: 39976582 DOI: 10.1021/acs.jmedchem.4c02840
Abstract

Acquired resistance in Cancer remains a significant challenge in oncology, posing obstacles to the efficacy of diverse therapeutic approaches. The nuclear factor-kappa B (NF-κB) signaling pathway plays an important role in the development of drug resistance in tumor cells. Herein, we employed NF-κB inhibitors and cisplatin to synthesize multitarget Pt(IV) antitumor prodrugs. Among them, the antiproliferation activity of complex 8 demonstrated a remarkable 146.92-time increase compared to cisplatin against A549/CDDP cells. Moreover, complex 8 could effectively induce DNA damage, promote ROS generation, induce Autophagy, trigger the mitochondrial Apoptosis pathway, and suppress cell proliferation through the NF-κB signaling pathway. Furthermore, complex 8 effectively downregulated the levels of VEGF and HIF-1α and exerted antiproliferative activity through the PI3K/Akt and STAT-3 pathway in A549/CDDP cells. Interestingly, complex 8 showed a superior in vivo antitumor activity than cisplatin, 5a, or their combination, suggesting its potential as a promising candidate for further drug development in lung Cancer treatment.

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