Synthesis, characterization, and antitumor activity of three ternary dinuclear copper (II) complexes with a reduced Schiff base ligand and diimine coligands in vitro and in vivo

J Inorg Biochem. 2016 Jun:159:107-19. doi: 10.1016/j.jinorgbio.2016.02.033. Epub 2016 Mar 4.

Abstract

Three ternary copper (II) complexes containing 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), with the formulation [Cu2(NCL)2(H4PASP)]·4.5H2O (1-3) (where NCL=the diimine coligand, H4PASP=N,N'-(p-xylylene)di-2-aminosuccinic acid), were isolated and characterized. The binding of these complexes with calf thymus DNA was studied using UV-visible absorption titration, emission, and circular dichroism spectroscopy, among other methods. The changes in physicochemical properties that occurred upon binding of these complexes with DNA indicate that binding occurs primarily through intercalative interactions. Human tumor cell lines HeLa, PC3, and HepG2 were treated with the copper(II) complexes in vitro and cell survival rate was assessed by 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet survival assay. Flow cytometry was performed on treated cells labeled with AnnexinV/Propidium Iodide staining to determine rates of apoptosis. Western blot was performed to determine the expression levels of the apoptotic markers p53, Bax, and Bcl-2. The complexes reduced cell viability and induced apoptosis in cells of human tumor cell lines in a dose-dependent manner. In addition, using a nude mouse xenograft model, we found that the three ternary copper (II) complexes inhibited human tumor cell growth in vivo. In conclusion, these novel synthetic copper complexes have profound antitumor effects on human tumor cells and are promising therapeutic agents for human tumors.

Keywords: Antitumor effects; Diimine coligands; Schiff base ligand; Ternary dinuclear copper(II) complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects*
  • Cattle
  • Copper* / chemistry
  • Copper* / pharmacology
  • DNA / chemistry
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Imines* / chemical synthesis
  • Imines* / chemistry
  • Imines* / pharmacology
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Schiff Bases / chemical synthesis
  • Schiff Bases / chemistry
  • Schiff Bases / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • BAX protein, human
  • BCL2 protein, human
  • Imines
  • Proto-Oncogene Proteins c-bcl-2
  • Schiff Bases
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Copper
  • DNA
  • calf thymus DNA