Azilsartan and its Zn(II) complex. Synthesis, anticancer mechanisms of action and binding to bovine serum albumin

• Published in: Toxicology in vitro Vol. 48; pp. 205 - 220
• Main Authors: Martínez, Valeria R., Aguirre, María V., Todaro, Juan S., Piro, Oscar E., Echeverría, Gustavo A., Ferrer, Evelina G., Williams, Patricia A.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2018; Elsevier Science Ltd
• Subjects: ACE inhibitors; Angiotensin; Angiotensin II; Anticancer mechanisms; Anticancer properties; Apoptosis; Azilsartan; Binding; Bovine serum albumin; BSA interactions; Cancer; Cells; Crystal structure; Cytotoxicity; Fibroblasts; Hypertension; Lung cancer; Medical treatment; Mitochondria; Nitrogen atoms; Oxidative stress; Serum albumin; Tumor cell lines; X-ray diffraction; Zinc; Zn(II)-Azilsartan complex; DMSO; H2DCFDA; MTT; BSA; DMEM; ZnAzil; OPT; Zn(II)-Azilsartan complex; FBS; RIPA buffer; GSH; EtBr; 4CN; PBS; GSSG; Azil; SDS; DCF; PAGE; EDTA; Zincon; Ang II; AO; EGTA; Anticancer mechanisms; BSA interactions; NAC; Azilsartan; Bcl-xL; PMSF; NEM; ROS; Bax; ARBs
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2018.01.009

Azilsartan is the eighth approved member of angiotensin II receptor blockers for hypertension treatment. Considering that some drugs have additional effects when administered, we studied its effects and mechanisms of action on a human lung cancer cell line A549. We have also modified the structure of the drug by complexation with Zn(II) cation and assayed the anticancer effect. The crystal structure of the new binuclear Zn(II) complex, for short [Zn2(azil)2(H2O)4]·2H2O (ZnAzil), was determined by X-ray diffraction methods. The zinc ions are bridged by azilsartan ligands through their carboxylate oxygen and oxadiazol nitrogen atoms. The compounds were examined for their cytotoxic effects against human lung fibroblast (MRC5) and human lung cancer (A549) cell lines. Azilsartan displayed low cytotoxic effects at 150 μM concentrations in A549 human lung cancer cells but the higher effect measured for the Zn complex suggested that this compound may act as an anticancer agent. An apoptotic oxidative stress mechanism of action via the mitochondrial-dependent intrinsic pathway has been determined. Besides, the compounds exerted weak cytotoxic effects in the normal lung related cell line MRC5. Binding constants of the complex formed between each compound and bovine serum albumin (BSA) are in the intermediate range, hence suggesting that azilsartan and ZnAzil could be bonded and transported by BSA. Study of a Zn complex with the designed antihypertensive drug, azilsartan, and their potential anticancer applications. [Display omitted] •Study of a Zn complex with the designed antihypertensive drug, azilsartan•Cytotoxicity against human lung cancer A549 cell lines•No interference on human lung fibroblast MRC5 cell line viability•Oxidative stress mediated apoptosis via intrinsic pathway evaluated by Western blot.•Azilsartan and the complex interacted with bovine serum albumin.