Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00492426" target="_blank" >RIV/68081707:_____/18:00492426 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/18:73589819

Výsledek na webu

<a href="http://dx.doi.org/10.1002/chem.201705362" target="_blank" >http://dx.doi.org/10.1002/chem.201705362</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/chem.201705362" target="_blank" >10.1002/chem.201705362</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents

Popis výsledku v původním jazyce

A series of five kinetically inert bis-cyclometalated Ir-III complexes of general formula [Ir(C boolean AND N)(2)(N boolean AND N)][PF6] [C boolean AND N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-N,C, N boolean AND N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2,3-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2,3-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2,3-c]phenazine (dppn, 4), and dipyrido[3,2-a:2,3-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC50) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (approximate to 10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing.

Název v anglickém jazyce

Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents

Popis výsledku anglicky

A series of five kinetically inert bis-cyclometalated Ir-III complexes of general formula [Ir(C boolean AND N)(2)(N boolean AND N)][PF6] [C boolean AND N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-N,C, N boolean AND N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2,3-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2,3-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2,3-c]phenazine (dppn, 4), and dipyrido[3,2-a:2,3-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC50) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (approximate to 10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

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

Chemistry - A European Journal

ISSN

0947-6539

e-ISSN

—

Svazek periodika

24

Číslo periodika v rámci svazku

18

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

13

Strana od-do

4607-4619

Kód UT WoS článku

000428378300021

EID výsledku v databázi Scopus

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