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

Result code in 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>

Alternative codes found

RIV/61989592:15310/18:73589819

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2018

Confidentiality

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

Name of the periodical

Chemistry - A European Journal

ISSN

0947-6539

e-ISSN

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Volume of the periodical

24

Issue of the periodical within the volume

18

Country of publishing house

DE - GERMANY

Number of pages

13

Pages from-to

4607-4619

UT code for WoS article

000428378300021

EID of the result in the Scopus database

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