2. Academic Validation
  3. Novel Indole-Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

Novel Indole-Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

  • J Med Chem. 2023 Apr 13;66(7):4868-4887. doi: 10.1021/acs.jmedchem.2c02036.
Zhikun Liu 1,  Meng Wang 1 2,  Rizhen Huang 3,  Tianhui Hu 4,  Yi Jing 1,  Xiaochao Huang 1,  Weiwei Hu 1,  Guoxiu Cao 1,  Hengshan Wang 2
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, 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 for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
  • 4 Traditional Chinese Medicine Department, Huai'an Maternal and Child Health-Care Center, Huai'an 2230003, China.
PMID: 36946996 DOI: 10.1021/acs.jmedchem.2c02036
Abstract

Developing multifunctional platinum(IV) prodrugs via integrating bioactive pharmacophores into one entity is an attractive strategy to ameliorate the defects of platinum(II) drugs. Herein, a series of indole-chalcone derivative-ligated platinum(IV) complexes were synthesized and evaluated for their Anticancer activities. Among them, optimal complex 17a exerted superior activity compared to that of cisplatin (CDDP) against the tested cells but showed lower cytotoxicity toward human normal lung cells. Detailed mechanisms demonstrated that 17a significantly enhanced intracellular accumulation, induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, 17a efficiently disturbed the tubulin-microtubule system, initiated Reactive Oxygen Species (ROS)-mediated endoplasmic reticulum stress, and activated a mitochondrion-dependent Apoptosis signaling pathway. Besides, 17a was superior to free drugs or their combination in inhibiting Cancer growth in A549/CDDP xenografts without inducing obvious side effects. The physical mixture of 16a and CDDP was almost identical to 17a but showed apparent systematic side effects. In summary, our studies may provide an efficient treatment regimen for CDDP resistance.

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