JBIC Journal of Biological Inorganic Chemistry

, Volume 21, Issue 7, pp 851–863 | Cite as

Experimental and DFT characterization, antioxidant and anticancer activities of a Cu(II)–irbesartan complex: structure–antihypertensive activity relationships in Cu(II)–sartan complexes

  • María S. Islas
  • Alicia Luengo
  • Carlos A. Franca
  • Mercedes Griera Merino
  • Laura Calleros
  • Manuel Rodriguez-Puyol
  • Luis Lezama
  • Evelina G. Ferrer
  • Patricia A. M. Williams
Original Paper

Abstract

The coordination compound of the antihypertensive ligand irbesartan (irb) with copper(II) (CuIrb) was synthesized and characterized by FTIR, FT-Raman, UV–visible, reflectance and EPR spectroscopies. Experimental evidence allowed the implementation of structural and vibrational studies by theoretical calculations made in the light of the density functional theory (DFT). This compound was designed to induce structural modifications on the ligand. No antioxidant effects were displayed by both compounds, though CuIrb behaved as a weak 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·) scavenger (IC50 = 425 μM). The measurements of the contractile capacity on human mesangial cell lines showed that CuIrb improved the antihypertensive effects of the parent medication. In vitro cell growth inhibition against prostate cancer cell lines (LNCaP and DU 145) was measured for CuIrb, irbesartan and copper(II). These cell lines have been selected since the angiotensin II type 1 (AT1) receptor (that was blocked by the angiotensin receptor blockers, ARB) has been identified in them. The complex exerted anticancer behavior (at 100 μM) improving the activity of the ligand. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death.

Graphical Abstract

Experimental and DFT characterization of an irbesartan copper(II) complex has been performed. The complex exhibits low scavenging activity against DPPH· and significant growth inhibition of LNCaP and DU 145 prostate cancer cell lines. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. This compound improved the antihypertensive effect of irbesartan. This effect was observed earlier for the mononuclear Cu–candesartan complex, but not in structurally modified sartans forming dinuclear or octanuclear Cu–sartan compounds.

Keywords

Irbesartan Copper(II) complex Antioxidant Antihypertensive Cytotoxicity 

Abbreviations

ABTS

2,2′-Azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid diammonium salt)

Ang II

Angiotensin II

ARBs

AT1 receptor blockers

AT1

Ang II type 1 receptor

CuIrb

[Cu(Irb)2(H2O)], Irb: irbesartan

DPPH.

1,1-Diphenyl-2-picrylhydrazyl radical

DTA

Differential thermal analysis

HMC

Human mesangial cells

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NBT

Nitroblue tetrazolium

PBS

Phosphate buffered saline

PCSA

Planar cell surface area

PI

Propidium iodide

RAS

Renin–angiotensin system

SOD

Superoxide dismutase

TGA

Thermogravimetric analysis

Supplementary material

775_2016_1384_MOESM1_ESM.pdf (72 kb)
Fig S1. Thermogram of the solid [Cu(Irb)2(H2O)] complex. O2 flow: 60 mL/min; heating rate: 10 °C/min (PDF 72 kb)

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Copyright information

© SBIC 2016

Authors and Affiliations

  • María S. Islas
    • 1
  • Alicia Luengo
    • 3
    • 4
  • Carlos A. Franca
    • 1
  • Mercedes Griera Merino
    • 3
    • 4
  • Laura Calleros
    • 3
    • 4
  • Manuel Rodriguez-Puyol
    • 3
    • 4
  • Luis Lezama
    • 2
  • Evelina G. Ferrer
    • 1
  • Patricia A. M. Williams
    • 1
  1. 1.Facultad de Ciencias Exactas, Centro de Química Inorgánica (CEQUINOR/CONICET/UNLP)Universidad Nacional de La PlataLa PlataArgentina
  2. 2.Departamento de Química Inorgánica, Facultad de Ciencia y TecnologíaUniversidad del País VascoBilbaoSpain
  3. 3.Department of Systems Biology, Physiology Unity, Medicine SchoolUniversity of AlcaláMadridSpain
  4. 4.IRSIN and REDinREN (Instituto de Salud Carlos III)MadridSpain

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