The Pt(IV) complexes of norcantharidin axial-modulated by carboxylic acid ligand: Synthesis, characterization, in vitro/in vivo anticancer efficacy and hypoxic activity.

Norcantharidin (NCTD), a semi-synthetic derivative of cantharidin from the animal-derived traditional Chinese medicine Cantharides, was selected as a potential functional anticancer ligand. Then three new Pt(IV) complexes (Pt-NCTD-bu, Pt-NCTD-pe, Pt-NCTD-he) were designed as a homologous series to evaluate how increasing axial chain length affects lipophilicity and anticancer efficacy. The axial carboxylate ligands were employed to modulate lipophilicity and coordination stability. These complexes exhibited stronger cytotoxicity against the most sensitive A2780 cells than cisplatin, with the order of potency following he > pe > bu, correlating with increasing lipophilicity and cellular uptake. All three complexes also effectively suppressed colony formation. They also overcame cisplatin resistance in A2780/CDDP cells. Mechanistically, they could release active Pt(II) and NCTD via GSH-mediated reduction, inducing ROS accumulation, mitochondrial dysfunction, DNA damage and cell apoptosis. Especially, under intracellular hypoxia condition, Pt-NCTD-he showed the highest oxygen-independent cytotoxicity. In vivo, Pt-NCTD-he (20 mg/kg) more effectively suppressed tumor growth in A2780 xenografts than cisplatin, with a 70.0% inhibition rate. Pt-NCTD-he was found to mainly distribute in the liver, indicating that a higher lipophilicity is conducive to better anticancer activity. Pt-NCTD-he also showed satisfactory pharmacokinetic properties, with a longer elimination half-life (1.3 h) than cisplatin (ca. 0.5 h). This work highlights the rational design of Pt(IV) complexes by integrating natural medicinal ingredients, providing a promising strategy for the new generation of Pt(IV)-based complexes as anticancer prodrugs.