Discovery of Pt( <scp>ii</scp> ) complexes based on a terpyridine skeleton and study of their antiproliferative activity against pancreatic cancer cells

A novel platinum(II) complex based on a terpyridine skeleton was developed to achieve a metal complex that interacts with the DNA of tumor cells with higher affinity. 1-(4-([2,2':6',2''-Terpyridin]-4'-yl)phenyl)piperidine-4-carboxylic acid (CPT) was selected as the organic ligand, and a complex of CPT and Pt (CPT-Pt) was afforded through a hydrothermal approach. The MTT assay demonstrated that CPT-Pt exhibited higher antiproliferation against BxPC-3 cells with an IC₅₀ value of 6.26 μM. Moreover, the apoptosis rate of BxPC-3 cells in the CPT-Pt group was up to 77.5% at 30 μM, which was 1.7-fold higher than that of the oxaliplatin group, as tested using flow cytometry. CPT-Pt arrested BxPC-3 cells at the G2 phase in cell cycle progression. The molecular mechanism study showed that CPT-Pt promoted the accumulation of intracellular ROS and induced the loss of mitochondrial membrane potential. The results of UV absorption spectra, fluorescence spectra and molecular docking showed that CPT-Pt interacted with DNA through hydrogen bonds. Moreover, DNA cleavage was observed through gel electrophoresis. In a xenograft pancreatic cancer model, the tumor volume in the CPT-Pt group decreased by 75%, indicating that CPT-Pt effectively inhibited tumor growth <i>in vivo</i>. These findings provide a practical strategy for the rational design of novel Pt(II) complexes to improve their preclinical therapy of pancreatic cancer.