An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

Samuel M. Meier-Menches; Benjamin Neuditschko; Katja Zappe; Martin Schaier; Marlene C. Gerner; Klaus G. Schmetterer; Giorgia Del Favero; Riccardo Bonsignore; Margit Cichna-Markl; Gunda Koellensperger; Angela Casini; Christopher Gerner

doi:10.1002/chem.202003495

An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

Samuel M. Meier-Menches (Corresponding author)
, Benjamin Neuditschko
, Katja Zappe
, Martin Schaier
, Marlene C. Gerner
, Klaus G. Schmetterer
, Giorgia Del Favero
, Riccardo Bonsignore
, Margit Cichna-Markl
, Gunda Koellensperger
, Angela Casini (Corresponding author)
, Christopher Gerner (Corresponding author)

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

The organometallic Au-I bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)(2)](+) (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometrybased methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal- based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.

Original language	English
Pages (from-to)	15528-15537
Number of pages	10
Journal	Chemistry: A European Journal
Volume	26
Issue number	67
DOIs	https://doi.org/10.1002/chem.202003495
Publication status	Published - 1 Dec 2020

Funding

S.M. and C.G. receive support from the Austrian Science Fund (FWF): P33238-N. The authors are grateful for the support of the Core Facility of Mass Spectrometry, the Core Facility Multimodal Imaging (Faculty of Chemistry) and the Joint Metabolome Facility, members of the Vienna Life-Science Instruments (VLSI). Authors acknowledge the help of Julia Brunmair with the measurements on the Q Exactive HF. Open access funding enabled and organized by Projekt DEAL.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

104003 Inorganic chemistry
104015 Organic chemistry
301904 Cancer research

Keywords

cancer
gold complexes
G-quadruplexes
N-heterocyclic carbenes
proteomics
telomeres
NHC COMPLEXES
ANTICANCER AGENTS
G-QUADRUPLEX
RESPONSES
TELOMERASE
REGULATOR
MECHANISM
INSIGHTS
LIGANDS
BINDING

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10.1002/chem.202003495

Cite this

Meier-Menches, S. M., Neuditschko, B., Zappe, K., Schaier, M., Gerner, M. C., Schmetterer, K. G., Del Favero, G., Bonsignore, R., Cichna-Markl, M., Koellensperger, G., Casini, A., & Gerner, C. (2020). An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells. Chemistry: A European Journal, 26(67), 15528-15537. https://doi.org/10.1002/chem.202003495

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title = "An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells",

abstract = "The organometallic Au-I bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)(2)](+) (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometrybased methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal- based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.",

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year = "2020",

month = dec,

day = "1",

doi = "10.1002/chem.202003495",

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Meier-Menches, SM, Neuditschko, B, Zappe, K, Schaier, M, Gerner, MC, Schmetterer, KG, Del Favero, G, Bonsignore, R, Cichna-Markl, M , Koellensperger, G, Casini, A & Gerner, C 2020, 'An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells', Chemistry: A European Journal, vol. 26, no. 67, pp. 15528-15537. https://doi.org/10.1002/chem.202003495

TY - JOUR

T1 - An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

AU - Meier-Menches, Samuel M.

AU - Neuditschko, Benjamin

AU - Zappe, Katja

AU - Schaier, Martin

AU - Gerner, Marlene C.

AU - Schmetterer, Klaus G.

AU - Del Favero, Giorgia

AU - Bonsignore, Riccardo

AU - Cichna-Markl, Margit

AU - Koellensperger, Gunda

AU - Casini, Angela

AU - Gerner, Christopher

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The organometallic Au-I bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)(2)](+) (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometrybased methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal- based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.

AB - The organometallic Au-I bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)(2)](+) (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometrybased methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal- based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.

KW - cancer

KW - gold complexes

KW - G-quadruplexes

KW - N-heterocyclic carbenes

KW - proteomics

KW - telomeres

KW - NHC COMPLEXES

KW - ANTICANCER AGENTS

KW - G-QUADRUPLEX

KW - RESPONSES

KW - TELOMERASE

KW - REGULATOR

KW - MECHANISM

KW - INSIGHTS

KW - LIGANDS

KW - BINDING

UR - https://www.scopus.com/pages/publications/85096654701

U2 - 10.1002/chem.202003495

DO - 10.1002/chem.202003495

M3 - Article

SN - 0947-6539

VL - 26

SP - 15528

EP - 15537

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 67

ER -

An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

Access to Document

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