N-Indolyl diiron vinyliminium complexes exhibit
antiproliferative effects in cancer cells associated with
disruption of mitochondrial homeostasis, ROS scavenging, and
antioxidant activity

J 2023

N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity

BRESCIANI, Giulio, Jakub ČERVINKA, Hana KOSTRHUNOVÁ, Lorenzo BIANCALANA, Marco BORTOLUZZI et. al.

Basic information

Original name

N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity

Authors

BRESCIANI, Giulio (380 Italy), Jakub ČERVINKA (203 Czech Republic, belonging to the institution), Hana KOSTRHUNOVÁ (203 Czech Republic), Lorenzo BIANCALANA (380 Italy), Marco BORTOLUZZI (380 Italy), Guido PAMPALONI (380 Italy), Vojtěch NOVOHRADSKÝ (203 Czech Republic), Viktor BRABEC (203 Czech Republic), Fabio MARCHETTI (380 Italy) and Jana KAŠPÁRKOVÁ (203 Czech Republic)

Edition

Chemico-Biological Interactions, Elsevier B.V, 2023, 0009-2797

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.100 in 2022

RIV identification code

RIV/00216224:14310/23:00132046

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1016/j.cbi.2023.110742

UT WoS

001094243700001

Keywords in English

Diiron complexes; Indole; Anticancer; Mitochondria; ROS; Antioxidant

Abstract

V originále

The indole scaffold has been established as a key organic moiety for developing new drugs; on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2–5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2–6 are substantially stable in DMSO‑d6 and DMEM-d solutions at 37 °C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogPow values in the range −0.32 to 0.47), associated with appreciable water solubility. The complexes display selective antiproliferative potency towards several cancer cells in monolayer cultures, mainly in the low micromolar range, with reduced toxicity towards noncancerous epithelial cells. Thus, the cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceutical cisplatin. Comparing the antiproliferative activity obtained for complexes containing different ligands, we confirmed the importance of the indolyl group in the mechanism of antiproliferative activity of these complexes. Cell-based mechanistic studies suggest that the investigated diiron vinyliminium complexes (DVCs) show cytostatic rather than cytotoxic effects and subsequently induce a population of cells to undergo apoptosis. Furthermore, the molecular mechanism of action involves interactions with mitochondrial DNA and proteins, the reactive oxygen species (ROS)-scavenging properties and antioxidant activity of these complexes in cancer cells. This study highlights the importance of DVCs to their cancer cell activity and reinforces their prospective therapeutic potential as anticancer agents.

Citovat

BRESCIANI, Giulio, Jakub ČERVINKA, Hana KOSTRHUNOVÁ, Lorenzo BIANCALANA, Marco BORTOLUZZI, Guido PAMPALONI, Vojtěch NOVOHRADSKÝ, Viktor BRABEC, Fabio MARCHETTI and Jana KAŠPÁRKOVÁ. N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity. Chemico-Biological Interactions. Elsevier B.V, 2023, vol. 385, November, p. 1-15. ISSN 0009-2797. Available from: https://dx.doi.org/10.1016/j.cbi.2023.110742.

@article{2330527,
   author = {Bresciani, Giulio and Červinka, Jakub and Kostrhunová, Hana and Biancalana, Lorenzo and Bortoluzzi, Marco and Pampaloni, Guido and Novohradský, Vojtěch and Brabec, Viktor and Marchetti, Fabio and Kašpárková, Jana},
   article_number = {November},
   doi = {http://dx.doi.org/10.1016/j.cbi.2023.110742},
   keywords = {Diiron complexes; Indole; Anticancer; Mitochondria; ROS; Antioxidant},
   language = {eng},
   issn = {0009-2797},
   journal = {Chemico-Biological Interactions},
   title = {N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity},
   url = {https://doi.org/10.1016/j.cbi.2023.110742},
   volume = {385},
   year = {2023}
}

TY  - JOUR
ID  - 2330527
AU  - Bresciani, Giulio - Červinka, Jakub - Kostrhunová, Hana - Biancalana, Lorenzo - Bortoluzzi, Marco - Pampaloni, Guido - Novohradský, Vojtěch - Brabec, Viktor - Marchetti, Fabio - Kašpárková, Jana
PY  - 2023
TI  - N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity
JF  - Chemico-Biological Interactions
VL  - 385
IS  - November
SP  - 1-15
EP  - 1-15
PB  - Elsevier B.V
SN  - 00092797
KW  - Diiron complexes
KW  - Indole
KW  - Anticancer
KW  - Mitochondria
KW  - ROS
KW  - Antioxidant
UR  - https://doi.org/10.1016/j.cbi.2023.110742
N2  - The indole scaffold has been established as a key organic moiety for developing new drugs; on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2–5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2–6 are substantially stable in DMSO‑d6 and DMEM-d solutions at 37 °C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogPow values in the range −0.32 to 0.47), associated with appreciable water solubility. The complexes display selective antiproliferative potency towards several cancer cells in monolayer cultures, mainly in the low micromolar range, with reduced toxicity towards noncancerous epithelial cells. Thus, the cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceutical cisplatin. Comparing the antiproliferative activity obtained for complexes containing different ligands, we confirmed the importance of the indolyl group in the mechanism of antiproliferative activity of these complexes. Cell-based mechanistic studies suggest that the investigated diiron vinyliminium complexes (DVCs) show cytostatic rather than cytotoxic effects and subsequently induce a population of cells to undergo apoptosis. Furthermore, the molecular mechanism of action involves interactions with mitochondrial DNA and proteins, the reactive oxygen species (ROS)-scavenging properties and antioxidant activity of these complexes in cancer cells. This study highlights the importance of DVCs to their cancer cell activity and reinforces their prospective therapeutic potential as anticancer agents.
ER  -

BRESCIANI, Giulio, Jakub ČERVINKA, Hana KOSTRHUNOVÁ, Lorenzo BIANCALANA, Marco BORTOLUZZI, Guido PAMPALONI, Vojtěch NOVOHRADSKÝ, Viktor BRABEC, Fabio MARCHETTI and Jana KAŠPÁRKOVÁ. N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity. \textit{Chemico-Biological Interactions}. Elsevier B.V, 2023, vol.~385, November, p.~1-15. ISSN~0009-2797. Available from: https://dx.doi.org/10.1016/j.cbi.2023.110742.

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