Evaluation of the antioxidant, antihypertensive and antitumor activity of a Cu(II) and Irbesartan (Irb) complex [Cu(Irb)2(H2O)] (CuIrb): synthesis, characterization and DFT study.

MARÍA SOLEDAD ISLAS; CARLOS A. FRANCA; LUIS LEZAMA; TEÓFILO ROJO; MERCEDES GRIERA MERINO; MARÍA A. CORTÉZ; LAURA CALLEROS; MANUEL RODRIGUEZ PUYOL; EVELINA G. FERRER; PATRICIA A.M. WILLIAMS

Zurich

Conferencia; EUROBIC12; 2014

Irbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension [1]. Based on the fact that in some cases metal complexes displayed improved therapeutic properties compared to the parent drugs [2], we have synthesized a solid coordination Cu(II) complex with Irb and CuCl2 in ethanolic solution. Two different conformers of CuIrb, depending on the pH value of the preparative have been obtained; one of them was blue and insoluble in all tested solvents, and the other green one, was soluble in ethanol and DMSO. Both conformers were characterized by means of elemental analysis, thermal decomposition measurements, UV-vis, diffuse reflectance, infrared, Raman and EPR spectroscopies. Furthermore, the two possible structures for CuIrb have been determined by means of the Density Functional Theory (DFT). Besides, we have calculated the theoretical vibrational frequencies which allowed us to make comparisons with the experimental FTIR and Raman spectral data. Solution assays were performed only with the soluble conformer of CuIrb and stability studies under biological conditions and ethanolic solutions have been performed. The free radical scavenging capacities were measured on ABTS, DPPH, peroxyl radicals, and superoxide anion. While Irb was not able to scavenge any of these free radicals, CuIrb showed antioxidant activity against DPPH radicals. Moreover, we have tested the activity of the complex in different systems in vitro. The antihypertensive effects have been tested by the analysis of the inhibition of the activity of angiotensin II (Ang II) to reduce the planar cell surface area in human mesangial cells pretreated with Irb, CuIrb, and CuCl2. Surprisingly, the inhibition of contraction induced by AngII under CuIrb treatment has been increased (18 %), compared to the parent drug. On the other hand, we have tested the antitumor activity by means of MTT and cell cycle assays, in three prostate cancer cell lines: LNCaP, PC3 and DU145. We did not observe significant differences compared to basal conditions in concentrations up to 100 M.