Cell‐based studies of the first‐in‐class half‐sandwich Ir(III) complex containing histone deacetylase inhibitor 4‐phenylbutyrate. (11th January 2018)

• Record Type: Journal Article
• Authors: Štarha, Pavel; Trávníček, Zdeněk; Drahoš, Bohuslav; Herchel, Radovan; Dvořák, Zdeněk
• Is Part Of: Applied organometallic chemistry. Volume 32:Number 4(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-01-11
• Subjects: 4‐phenylbutyrate -- cytotoxicity -- flow cytometry -- half‐sandwich -- iridium(III) complexes; Organometallic chemistry -- Periodicals; Organometallic compounds -- Periodicals; 547.05
• DOI: 10.1002/aoc.4246
• Languages: English
• ISSNs: 0268-2605

Abstract

Abstract : We report on a cytotoxic half‐sandwich iridium(III) complex [Ir(η 5 ‐Cp ph )(phen)(PB)]PF6 (1‐PB ), containing a monodentate coordinated O ‐donor 4‐phenylbutyrato ligand (PB) belonging to the family of histone deacetylase inhibitors (HDACi); HCp ph = (2, 3, 4, 5‐tetramethylcyclopenta‐2, 4‐dien‐1‐yl)benzene, phen = 1, ​10‐phenanthroline. The solution behaviour studies indicated that complex1‐PB partially hydrolysed in the mixture of methanol and water (1:4, v/v ), resulting in the release of the PB ligand. The extent of the PB ligand release increased in the presence of 2 molar equiv. of the reduced glutathione (GSH). Complex1‐PB exhibited comparable in vitro cytotoxicity against the cisplatin ‐sensitive (IC50 = 15.8 μM) and ‐resistant (IC50 = 13.0 μM) variants of the A2780 human ovarian carcinoma cells, while its potency against the MRC‐5 human normal fibroblast cells was markedly lower (IC50 = 124.1 μM). The cytotoxicity studies revealed an ability of complex1‐PB to overcome the acquired resistance against cisplatin, with the resistance factor (RF = 0.8) being markedly lower than for complex1‐Cl (RF = 1.8) and cisplatin (RF = 2.9). The A2780 cell‐based flow cytometry experiments showed different cell cycle modification induced by complex1‐PB and cisplatin, induction of production of reactive oxygen species, and higher mitochondria membrane potential depleted cell populations after the treatment by complex1‐PB as compared with cisplatin . In the cell‐free assay, complex1‐PB inhibited the HDAC activity to ca 66% as compared to ca 74% valid for NaPB. The [Ir(η 5 ‐Cp ph )(phen)(H2 O)] 2+ species (1‐OH 2 ), representing the hydrolysis product of both complexes1‐PB and1‐Cl, induced hydroxyl radical from the hydrogen peroxide, as proved by the EPR spin trapping studies with the 5‐(diethoxyphosphoryl)‐5‐methyl‐1‐pyrroline‐ N ‐oxide (DEPMPO) spin trap. Abstract : Exchange of the chlorido ligand by the HDAC inhibitor 4‐phenylbutyrate (PB) in [Ir(η 5 ‐Cp ph )(phen)(PB)]PF6 improved cytotoxicity against A2780 and A2780R cells.