期刊
MOLECULAR PHARMACEUTICS
卷 17, 期 8, 页码 3009-3023出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.0c00417
关键词
translocator protein; Pt(IV) prodrugs; oxaliplatin; cisplatin; cytotoxicity; DNA damage
资金
- Precision Oncology Ireland
- Science Foundation Ireland Strategic Partnership Programme [18/SPP/3522]
- EU [H2020 MSCA RISE-734749, H2020MSCA-IF-2016 (TSPO METALLODRUGS.REP-7496211)]
- Science Foundation Ireland Principal Investigator award [13/IA/1954]
- Science Foundation Ireland (SFI) [13/IA/1954] Funding Source: Science Foundation Ireland (SFI)
The design, synthesis, characterization, and biological activity of a series of platinum(IV) prodrugs containing the axial ligand 3-(4-phenylquinazoline-2-carboxamido)propanoate (L3) are reported. L3 is a derivative of the quinazolinecarboxamide class of ligands that binds to the translocator protein (TSPO) at the outer mitochondrial membrane. The cytotoxicities of cis,cis,trans-[Pt(NH3)(2)Cl-2(L3)-(OH)] (C-Pt1), cis,cis,trans-[Pt-(NH3)(2)Cl-2(L3)(BZ)] (C-Pt2), trans-[Pt(DACH) (OX)(L3)(OH)] (C-Pt3), and trans-[Pt(DACH)(OX)(L3)(BZ)] (C-Pt4) (DACH: R,R-diaminocyclohexane, BZ: benzoate, OX: oxalate) in MCF-7 breast cancer and noncancerous MCF-10A epithelial cells were assessed and compared with those of cisplatin, oxaliplatin, and the free ligand L3. Moreover, the cellular uptake, ROS generation, DNA damage, and the effect on the mitochondrial function, mitochondrial membrane potential, and morphology were investigated. Molecular interactions of L3 in the TSPO binding site were studied using molecular docking. The results showed that complex C-Pt1 is the most effective Pt(IV) complex and exerts a multimodal mechanism involving DNA damage, potent ROS production, loss of the mitochondrial membrane potential, and mitochondrial damage.
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