1292280-55-7Relevant academic research and scientific papers
Cell-based studies of the first-in-class half-sandwich Ir(III) complex containing histone deacetylase inhibitor 4-phenylbutyrate
?tarha, Pavel,Trávní?ek, Zdeněk,Draho?, Bohuslav,Herchel, Radovan,Dvo?ák, Zdeněk
, (2018)
We report on a cytotoxic half-sandwich iridium(III) complex [Ir(η5-Cpph)(phen)(PB)]PF6 (1-PB), containing a monodentate coordinated O-donor 4-phenylbutyrato ligand (PB) belonging to the family of histone deacetylase inhibitors (HDACi); HCpph = (2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)benzene, phen = 1,?10-phenanthroline. The solution behaviour studies indicated that complex 1-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). Complex 1-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 complex 1-PB to overcome the acquired resistance against cisplatin, with the resistance factor (RF = 0.8) being markedly lower than for complex 1-Cl (RF = 1.8) and cisplatin (RF = 2.9). The A2780 cell-based flow cytometry experiments showed different cell cycle modification induced by complex 1-PB and cisplatin, induction of production of reactive oxygen species, and higher mitochondria membrane potential depleted cell populations after the treatment by complex 1-PB as compared with cisplatin. In the cell-free assay, complex 1-PB inhibited the HDAC activity to ca 66% as compared to ca 74% valid for NaPB. The [Ir(η5-Cpph)(phen)(H2O)]2+ species (1-OH2), representing the hydrolysis product of both complexes 1-PB and 1-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.
