Design, synthesis and characterization of tin-based cancer chemotherapy drug entity: In vitro DNA binding, cleavage, induction of cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation and molecular docking

摘要

A new organotin complex derived from propyl gallate and 1,10-phenanthroline was designed, synthesized and characterized using spectroscopic and elemental analytical methods. The underlying mechanisms of the anticancer action of the tin complex were further elucidated by evaluating its in vitro DNA interaction and the regulating signaling pathways. Our results showed that the tin complex could effectively activate DNA strand breaks in MCF-7 cells in a dose-dependent manner after cellular internalization. Phosphorylation of a DNA damage marker, histone H2A.X (Ser139), was thus upregulated in treated cells. Additionally, our results indicate that p53 is phosphorylated in response to DNA damage, and that this phosphorylation may be involved in the subsequent induction and activation of p53. In vitro DNA binding of the complex in Tris-HCl buffer was studied using various biophysical methods, revealing that the tin complex binds to DNA non-covalently via electrostatic interaction. The higher K-b value of the complex suggested greater DNA binding propensity. Further, to evaluate the mode of action at the molecular level, interaction studies of the tin complex with nucleotide (5 '-GMP) were carried out. The complex exhibits DNA cleavage activity with supercoiled pBR322 in the presence of different activators. The complex cleaves DNA efficiently via oxidative cleavage pathway. Molecular docking studies were performed to understand the binding mode of the tin complex with DNA (PDB ID: 1BNA).