Azilsartan and its Zn(II) complex. Synthesis, anticancer mechanisms of action and binding to bovine serum albumin. (April 2018)

• Record Type: Journal Article
• Authors: Martínez, Valeria R.; Aguirre, María V.; Todaro, Juan S.; Piro, Oscar E.; Echeverría, Gustavo A.; Ferrer, Evelina G.; Williams, Patricia A.M.
• Is Part Of: Toxicology in vitro. Volume 48(2018)
• Page Start: 205
• Page End: 220
• Publication Date: 2018-04
• Subjects: 4CN 4-chloro-1-naphthol -- Ang II angiotensin II -- AO acridine orange -- ARBs angiotensin receptor blockers -- Azil azilsartan -- Bax Bcl-2-associated X protein -- Bcl-xL B-cell lymphoma-extra large -- BSA bovine serum albumin -- DCF 2′, 7′-dichlorofluorescein -- DMEM Dulbeco's modified Eagle's Medium -- DMSO dimethyl sulfoxide -- EDTA ethylenediaminetetraacetic acid -- EGTA ethylene glycol-bis(β-aminoethyl ether)-N, N, N′, N′-tetraacetic acid -- EtBr ethidium bromide -- FBS fetal bovine serum -- GSH reduced glutathione -- GSSG oxidized glutathione -- H2DCFDA 2′, 7′-dichlorodihydrofluorescein diacetate -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NAC N-acetylcysteine -- NEM N-ethyl maleimide -- OPT o-phthalaldehyde -- PAGE polyacrylamide gel electrophoresis -- PBS phosphate buffered saline -- PMSF phenylmethylsulfonyl fluoride -- RIPA buffer radioimmunoprecipitation assay buffer -- ROS reactive oxygen species -- SDS dodecyl sulfate -- Zincon 2-[2-[(Z)-N-[(E)-(6-oxo-3-sulfocyclohexa-2, 4-dien-1-ylidene)amino]-C-phenylcarbonimidoyl]hydrazinyl]benzoic acid -- ZnAzil [Zn2(azil)2(H2O)4]·2H2O; Azilsartan -- Zn(II)-Azilsartan complex -- Anticancer mechanisms -- BSA interactions; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.01.009
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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 (H2 O)4 ]·2H2 O (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. Graphical abstract: Study of a Zn complex with the designed antihypertensive drug, azilsartan, and their potential anticancer applications. Highlights: 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.