2. Academic Validation
  3. Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

  • J Med Chem. 2024 May 23;67(10):8020-8042. doi: 10.1021/acs.jmedchem.4c00144.
Xiaochao Huang 1 2,  Guimei Li 2,  Huifang Li 2,  Wentian Zhong 2,  Guiyang Jiang 1,  Jinyuan Cai 1,  Qingping Xiong 1,  Chuang Wu 1,  Kangning Su 1,  Rizhen Huang 3,  Shiliu Xu 2,  Zhikun Liu 1,  Meng Wang 1 2,  Hengshan Wang 2
Affiliations

Affiliations

  • 1 Institute of Green Chemistry and Process Enhancement Technology, National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Huaiyin Institute of Technology, Huai'an 223003, China.
  • 2 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, 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, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
PMID: 38727048 DOI: 10.1021/acs.jmedchem.4c00144
Abstract

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested Cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote Reactive Oxygen Species generation, activate endoplasmic reticulum stress, and eventually induce Apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger Autophagy and Ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for Cancer treatment.

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