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

Abstract

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 in vivo. These findings provide a practical strategy for the rational design of novel Pt(II) complexes to improve their preclinical therapy of pancreatic cancer.