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

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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.

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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

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Acknowledgments

This work was supported by UNLP, CONICET (PIP 0611), CICPBA and by ANPCyT (PICT2013 0569), Argentina and Grant Renal Research Network: FEDER funds ISCIII RETIC REDINREN RD012/20021/0006, by Grant from Fondo de Investigaciones Sanitarias (FIS/ISCIII PI11/01630 and PI14/02075) to DRP and (FIS/ISCIII PI14/01939) to MRP integrated into the National Plan of I + D + i and co-funded by FEDER and the Instituto de Salud Carlos III and by Instituto de Investigaciones Sanitarias Reina Sofía (IRSIN) and Fundación Renal Iñigo Álvarez de Toledo (FRIAT). EGF and PAMW are research fellows of CONICET and CICPBA, Argentina, respectively. MSI is a fellowship holder from CONICET.

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Authors and Affiliations

  1. Facultad de Ciencias Exactas, Centro de Química Inorgánica (CEQUINOR/CONICET/UNLP), Universidad Nacional de La Plata, Bv. 120 e/ 60 y 64 Nº1465, 1900, La Plata, Argentina

    María S. Islas, Carlos A. Franca, Evelina G. Ferrer & Patricia A. M. Williams

  2. Departamento de Química Inorgánica, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Apdo. 644, 48080, Bilbao, Spain

    Luis Lezama

  3. Department of Systems Biology, Physiology Unity, Medicine School, University of Alcalá, Alcalá de Henares, Madrid, Spain

    Alicia Luengo, Mercedes Griera Merino, Laura Calleros & Manuel Rodriguez-Puyol

  4. IRSIN and REDinREN (Instituto de Salud Carlos III), Madrid, Spain

    Alicia Luengo, Mercedes Griera Merino, Laura Calleros & Manuel Rodriguez-Puyol

Authors
  1. María S. Islas
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  2. Alicia Luengo
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  3. Carlos A. Franca
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  4. Mercedes Griera Merino
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  5. Laura Calleros
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  6. Manuel Rodriguez-Puyol
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  7. Luis Lezama
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  8. Evelina G. Ferrer
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  9. Patricia A. M. Williams
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Corresponding author

Correspondence to Patricia A. M. Williams.

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Islas, M.S., Luengo, A., Franca, C.A. et al. Experimental and DFT characterization, antioxidant and anticancer activities of a Cu(II)–irbesartan complex: structure–antihypertensive activity relationships in Cu(II)–sartan complexes. J Biol Inorg Chem 21, 851–863 (2016). https://doi.org/10.1007/s00775-016-1384-5

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  • DOI: https://doi.org/10.1007/s00775-016-1384-5

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