Antitumor (in vitro) and antihypertensive (in vivo) effects of a new coordination complex formed with the drug telmisartan and the biometal Zn(II)

V.R. MARTÍNEZ; M.V. AGUIRRE; J.S. TODARO; FERRER E.G; P.A.M. WILLIAMS

Birmingham

Conferencia; 14th Biennial Conference in Birmingham, EUROBIC14; 2018

School of Medicine, University of Birmingham

Considering that the biological activities of some drugs can be improved by their structural modification, the structure of the antihypertensive agent telmisartan (Tlm) was modified through its interaction with the biometal Zn. The obtained complex [Zn(Tlm)2].4H2O (ZnTlm) was characterized by elemental analysis, thermogravimetric determinations and spectroscopic techniques (FTIR, NMR). The antitumor activity was measured in the human lung cancer cell line A549 and the probable mechanisms of action were determined. The complex markedly improved the deleterious effect on the tumor line, with a value of IC50 of 75 μM (IC50 125 μM for telmisartan, IC50 225 μM for ZnSO4). The cellular oxidative stress generation for ZnTlm (increase in reactive oxygen species and decrease in cellular reducing species (glutathione/oxidized glutathione, GSH/GSSG)) induced an apoptotic mechanism: increase in the BAX/Bcl-XL ((pro-apoptotic protein)/(antiapoptotic protein)) ratio and caspase-3 activation. The complex generated 47.5% of apoptotic cells (TUNEL) and telmisartan induced 39% of necrosis (staining with acridine orange and ethidium bromide). Both the complex and the ligand bind to bovine serum albumin (BSA), the interaction of the complex being greater. The calculated binding constants were in the order of 105 M-1 and an electrostatic interaction mechanism was determined. Moreover, the ZnTlm complex produced a slightly higher blood pressure reduction than the antihypertensive drug telmisartan after 6 days of treatment. This effect was measured in a hypertensive rat model by chronic administration of L-NAME (N-Nitro-L-arginine methyl ester hydrochloride).