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. WilliamsEmail author
Original Paper


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.


Irbesartan Copper(II) complex Antioxidant Antihypertensive Cytotoxicity 



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

Ang II

Angiotensin II


AT1 receptor blockers


Ang II type 1 receptor


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


1,1-Diphenyl-2-picrylhydrazyl radical


Differential thermal analysis


Human mesangial cells


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


Nitroblue tetrazolium


Phosphate buffered saline


Planar cell surface area


Propidium iodide


Renin–angiotensin system


Superoxide dismutase


Thermogravimetric analysis



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.

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)


  1. 1.
    Garrido AM, Griendling KK (2009) Mol Cell Endocrinol 302:148–158CrossRefPubMedGoogle Scholar
  2. 2.
    Duncia JV, Chiu AT, Carini DJ, Gregory GB, Johnson AL, Price WA, Wells GJ, Wong PC, Calabrese JC, Timmermans PB (1990) J Med Chem 33:1312–1329CrossRefPubMedGoogle Scholar
  3. 3.
    Ram CVS (2008) Am J Med 121:656–663CrossRefPubMedGoogle Scholar
  4. 4.
    Fotakis C, Christodouleas D, Zoumpoulakis P, Kritsi E, Benetis N-P, Mavromoustakos T, Reis H, Gili A, Papadopoulos MG, Zervou M (2011) J Phys Chem B 115:6180–6192CrossRefPubMedGoogle Scholar
  5. 5.
    Potamitis C, Zervou M, Katsiaras V, Zoumpoulakis P, Kyrikou I, Argyropoulos D, Vatougia G, Mavromoustakos T (2009) J Chem Inform Model 49:726–739CrossRefGoogle Scholar
  6. 6.
    Franca CA, Etcheverry SB, Diez RP, Williams PAM (2009) J Raman Spectrosc 2009:1296–1300CrossRefGoogle Scholar
  7. 7.
    Abali H, Güllü IH, Engin H, Haznedaroğlu IC, Erman M, Tekuzman G (2002) Med Hypotheses 59:344–348CrossRefPubMedGoogle Scholar
  8. 8.
    Deshayes F, Nahmias C (2005) Trends Endocrinol Metab 16:293–299CrossRefPubMedGoogle Scholar
  9. 9.
    Arafat H, Gong Q, Chipitsyna G, Rizvi A, Saa CT, Yeo CJ (2007) J Am Coll Surg 204:996–1005 (discussion 1005–1006) CrossRefPubMedGoogle Scholar
  10. 10.
    Klevay LM, Ann NY (1980) Acad Sci 355:140–151CrossRefGoogle Scholar
  11. 11.
    Suliburska J, Bogdanski P, Jakubowski H (2014) Eur J Pharmacol 738:326–331CrossRefPubMedGoogle Scholar
  12. 12.
    Etcheverry SB, Ferrer EG, Naso L, Barrio DA, Lezama L, Rojo T, Williams PAM (2007) Bioorg Med Chem 15:6418–6424CrossRefPubMedGoogle Scholar
  13. 13.
    Etcheverry S, Di Virgilio AL, Nascimento OR, Williams PAM (2012) J Inorg Biochem 107:25–33CrossRefPubMedGoogle Scholar
  14. 14.
    Islas MS, Lezama L, Griera Merino M, Cortes MA, Rodriguez Puyol M, Ferrer EG, Williams PAM (2013) J Inorg Biochem 123:23–33CrossRefPubMedGoogle Scholar
  15. 15.
    Islas MS, Martínez Medina JJ, López Tévez LL, Rojo T, Lezama L, Griera Merino M, Calleros L, Cortes MA, Rodriguez Puyol M, Echeverría GA, Piro OE, Ferrer EG, Williams PAM (2014) Inorg Chem 53:5724–5737CrossRefPubMedGoogle Scholar
  16. 16.
    Chow L, Rezmann L, Imamura K, Wang L, Catt K, Tikellis C, Louis WJ, Frauman AG, Louis SNS (2008) Prostate 68:651–660CrossRefPubMedGoogle Scholar
  17. 17.
    Analytische Messtechnik-GmbH (1996) WINEPR SimFonia v1.25 software, BrukerGoogle Scholar
  18. 18.
    Zhao Y, Truhlar DG (2007) Theor Chem Acc 120:215–241CrossRefGoogle Scholar
  19. 19.
    Dunning TH, Hay PJ (1977) In: Schaefer HF (ed) Methods of electronic structure theory, vol 3. Plenum press, New YorkGoogle Scholar
  20. 20.
    Casida ME, Jamorski C, Casida KC, Salahub DRJ (1998) Chem Phys 108:4439–4449Google Scholar
  21. 21.
    Keresztury G, Holly S, Besenyei G, Varga J, Wang A, Durig JR (1993) Spectrochim Acta Part A Mol Spectrosc 49:2007–2026CrossRefGoogle Scholar
  22. 22.
    Cariaga-Martinez AE, López-Ruiz P, Nombela-Blanco MP, Motiño O, González-Corpas A, Rodriguez-Ubreva J, Lobo MVT, Cortés MA, Colás B (2013) Cell Signal 25:1586–1597CrossRefPubMedGoogle Scholar
  23. 23.
    Luo C, Li Y, Zhou B, Yang L, Li H, Feng Z, Li Y, Long J, Liu J (2014) Apoptosis 19:542–553CrossRefPubMedGoogle Scholar
  24. 24.
    Calleros L, Lasa M, Rodríguez-Álvarez F, Toro M, Chiloeches A (2006) Apoptosis 11:1161–1173CrossRefPubMedGoogle Scholar
  25. 25.
    Williams PAM, Ferrer EG, Correa MJ, Baran EJ, Castellano EE, Piro OE (2004) J Chem Crystallogr 34:285–290CrossRefGoogle Scholar
  26. 26.
    Dutta RL, Satapathi SK (1981) J Inorg Nucl Chem 43:1533–1539CrossRefGoogle Scholar
  27. 27.
    Lane TJ, Nakagawa I, Walter JL, Kandathil AJ (1962) Inorg Chem 1:267–276CrossRefGoogle Scholar
  28. 28.
    Klapötke TM, Schmid PC, Stierstorfer J, Szimhardt N (2016) Z Anorg Allg Chem 642:383–389CrossRefGoogle Scholar
  29. 29.
    Nakamoto K (2009) Infrared and Raman spectra of inorganic and coordination compounds, Part B, 6th edn. John Wiley and Sons Inc, New JerseyGoogle Scholar
  30. 30.
    van Albada GA, Quiroz-Castro ME, Mutikainen I, Turpeinen U, Reedijk J (2000) Inorg Chim Acta 298:221–225CrossRefGoogle Scholar
  31. 31.
    Tabbì G, Giuffrida A, Bonomo RP (2013) J Inorg Biochem 128:137–145CrossRefPubMedGoogle Scholar
  32. 32.
    Hathaway BJ, Billing DE (1970) Coord Chem Rev 5:143–207CrossRefGoogle Scholar
  33. 33.
    Yamaguchi T, Takamura H, Matoba T, Terao J (1998) Biosci Biotechnol Biochem 62:1201–1204CrossRefPubMedGoogle Scholar
  34. 34.
    Wang M, Zhao X, Gai C, Liu H, Xu Y, Li J (2011) Chem Res Chinese Univ 27:1–5CrossRefGoogle Scholar
  35. 35.
    Ohno K, Amano Y, Kakuta H, Niimi T, Takakura S, Orita M, Miyata K, Sakashita H, Takeuchi M, Komuro I, Higaki J, Horiuchi M, Kim-Mitsuyama S, Mori Y, Morishita R, Yamagishi S (2011) Biochem Biophys Res Commun 404:434–437CrossRefPubMedGoogle Scholar
  36. 36.
    Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, Touraine JL, Nakatani T, Yoshimura R (2008) Oncol Rep 20:295–300PubMedGoogle Scholar

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
    Email author
  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

Personalised recommendations