Cell-based studies of the first-in-class half-sandwich Ir(III) complex containing histone deacetylase inhibitor 4-phenylbutyrate

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F18%3A73591075" target="_blank" >RIV/61989592:15310/18:73591075 - isvavai.cz</a>

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/full/10.1002/aoc.4246" target="_blank" >https://onlinelibrary.wiley.com/doi/full/10.1002/aoc.4246</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/aoc.4246" target="_blank" >10.1002/aoc.4246</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Cell-based studies of the first-in-class half-sandwich Ir(III) complex containing histone deacetylase inhibitor 4-phenylbutyrate

Popis výsledku v původním jazyce

We report on a cytotoxic half-sandwich iridium(III) complex [Ir((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); 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 = 15.8M) and -resistant (IC50 = 13.0M) variants of the A2780 human ovarian carcinoma cells, while its potency against the MRC-5 human normal fibroblast cells was markedly lower (IC50 = 124.1M). 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((5)-Cp-ph)(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.

Název v anglickém jazyce

Cell-based studies of the first-in-class half-sandwich Ir(III) complex containing histone deacetylase inhibitor 4-phenylbutyrate

Popis výsledku anglicky

We report on a cytotoxic half-sandwich iridium(III) complex [Ir((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); 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 = 15.8M) and -resistant (IC50 = 13.0M) variants of the A2780 human ovarian carcinoma cells, while its potency against the MRC-5 human normal fibroblast cells was markedly lower (IC50 = 124.1M). 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((5)-Cp-ph)(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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

APPLIED ORGANOMETALLIC CHEMISTRY

ISSN

0268-2605

e-ISSN

—

Svazek periodika

32

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

"e4246-1"-"e4246-11"

Kód UT WoS článku

000428845800035

EID výsledku v databázi Scopus

2-s2.0-85040563163