Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor

Eur J Med Chem. 2018 Jan 1:143:1597-1603. doi: 10.1016/j.ejmech.2017.10.058. Epub 2017 Oct 25.

Abstract

A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, 1H and 13C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DAS + H)(NO3)2(H2O)]NO3·(H2O)·(CH3OH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI-H460, and MGC80-3 tumor cell lines, with IC50 values in 4.04-13.04 μM. The Hep-G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher in vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702 cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP-silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS.

Keywords: Cell apoptosis; Cu(II) complex; Dasatinib; Telomerase activity.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Copper / chemistry
  • Copper / pharmacology*
  • Crystallography, X-Ray
  • Dasatinib / chemistry
  • Dasatinib / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • G-Quadruplexes / drug effects
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / metabolism
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Copper
  • Telomerase
  • Dasatinib