Expanding Three-Coordinate Gold(I) Anticancer Agent Chemical Space

Charles E. Greif; Owamagbe N. Orobator; Chibuzor Olelewe; Sean Parkin; Samuel G. Awuah

doi:10.1021/acs.jmedchem.5c00608

Expanding Three-Coordinate Gold(I) Anticancer Agent Chemical Space

Charles E. Greif
, Owamagbe N. Orobator
, Chibuzor Olelewe
, Sean Parkin
, Samuel G. Awuah

Producción científica: Article › revisión exhaustiva

1 Cita (Scopus)

Resumen

We report the synthesis and characterization of 14 complexes of the type (Au(R)[N̂N])⁺, where R = tunable biaryldialkyl phosphine ligands and [N̂N] = bidentate phenanthroline derivatives as anticancer agents. These novel tricoordinate Au(I) complexes were characterized and evaluated in metabolically differentiated triple negative breast cancer (TNBC) cell lines for their cytotoxicity potential. The complexes demonstrated submicromolar cytotoxic activity against human breast cancer cells MDA-MB-231 or MDA-MB-468 with IC₅₀’s in the range of 0.4–5.0 μM. Complex 2e shows high potency in vitro and decreases 3D-breast cancer mammosphere viability. Mechanistic studies show 2e promotes cell death by apoptosis with plausible mode of action via endoplasmic reticulum stress induction. Tumor growth inhibition in a metastatic TNBC mouse model was observed, demonstrating 2e′s translational capability. We show for the first time the in vivo anticancer potential of a phosphine-supported tricoordinate-Au(I) complex in mice with suitable tolerability. These studies further expand the therapeutic potential of tricoordinate-Au(I) complexes.

Idioma original	English
Páginas (desde-hasta)	15669-15682
Número de páginas	14
Publicación	Journal of Medicinal Chemistry
Volumen	68
N.º	15
DOI	https://doi.org/10.1021/acs.jmedchem.5c00608
Estado	Published - ago 14 2025

Nota bibliográfica

Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society

Financiación

We are grateful for financial support from the National Institute of Health (NIH) P20GM130456 (S.G.A.). We would like to thank the following facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. The UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments, we would like to thank UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). We thank Dr. Chris Richard’s lab for access and assistance with fluorescence microscopy. This work and S.G.A. was supported by grant R01CA258421-01 from the National Cancer Institute. We are grateful for financial support from the National Institute of Health (NIH) P20GM130456 (S.G.A.). We would like to thank the following facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. The UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments, we would like to thank UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). We thank Dr. Chris Richard’s lab for access and assistance with fluorescence microscopy.

Financiadores	Número del financiador
University of Kentucky Markey Comprehensive Cancer Center
Office of the Vice President for Research
NSF
Office of the Executive Vice President for Research and Partnerships, Purdue University
Markey Cancer Center
Columbus NCI	P30 CA177558
National Institute of Health National Institute of Minority and Health Disparities Loan Repayment Program	P20GM130456
National Institutes of Health (NIH)	P20GM130456
National Science Foundation Arctic Social Science Program	CHE-997738, CHE-1625732
National Childhood Cancer Registry – National Cancer Institute	P30 CA177558, R01CA258421-01

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Expanding Three-Coordinate Gold(I) Anticancer Agent Chemical Space",

abstract = "We report the synthesis and characterization of 14 complexes of the type (Au(R)[{\^N}N])+, where R = tunable biaryldialkyl phosphine ligands and [{\^N}N] = bidentate phenanthroline derivatives as anticancer agents. These novel tricoordinate Au(I) complexes were characterized and evaluated in metabolically differentiated triple negative breast cancer (TNBC) cell lines for their cytotoxicity potential. The complexes demonstrated submicromolar cytotoxic activity against human breast cancer cells MDA-MB-231 or MDA-MB-468 with IC50{\textquoteright}s in the range of 0.4–5.0 μM. Complex 2e shows high potency in vitro and decreases 3D-breast cancer mammosphere viability. Mechanistic studies show 2e promotes cell death by apoptosis with plausible mode of action via endoplasmic reticulum stress induction. Tumor growth inhibition in a metastatic TNBC mouse model was observed, demonstrating 2e′s translational capability. We show for the first time the in vivo anticancer potential of a phosphine-supported tricoordinate-Au(I) complex in mice with suitable tolerability. These studies further expand the therapeutic potential of tricoordinate-Au(I) complexes.",

author = "Greif, \{Charles E.\} and Orobator, \{Owamagbe N.\} and Chibuzor Olelewe and Sean Parkin and Awuah, \{Samuel G.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

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AU - Orobator, Owamagbe N.

AU - Olelewe, Chibuzor

AU - Parkin, Sean

AU - Awuah, Samuel G.

PY - 2025/8/14

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N2 - We report the synthesis and characterization of 14 complexes of the type (Au(R)[N̂N])+, where R = tunable biaryldialkyl phosphine ligands and [N̂N] = bidentate phenanthroline derivatives as anticancer agents. These novel tricoordinate Au(I) complexes were characterized and evaluated in metabolically differentiated triple negative breast cancer (TNBC) cell lines for their cytotoxicity potential. The complexes demonstrated submicromolar cytotoxic activity against human breast cancer cells MDA-MB-231 or MDA-MB-468 with IC50’s in the range of 0.4–5.0 μM. Complex 2e shows high potency in vitro and decreases 3D-breast cancer mammosphere viability. Mechanistic studies show 2e promotes cell death by apoptosis with plausible mode of action via endoplasmic reticulum stress induction. Tumor growth inhibition in a metastatic TNBC mouse model was observed, demonstrating 2e′s translational capability. We show for the first time the in vivo anticancer potential of a phosphine-supported tricoordinate-Au(I) complex in mice with suitable tolerability. These studies further expand the therapeutic potential of tricoordinate-Au(I) complexes.

AB - We report the synthesis and characterization of 14 complexes of the type (Au(R)[N̂N])+, where R = tunable biaryldialkyl phosphine ligands and [N̂N] = bidentate phenanthroline derivatives as anticancer agents. These novel tricoordinate Au(I) complexes were characterized and evaluated in metabolically differentiated triple negative breast cancer (TNBC) cell lines for their cytotoxicity potential. The complexes demonstrated submicromolar cytotoxic activity against human breast cancer cells MDA-MB-231 or MDA-MB-468 with IC50’s in the range of 0.4–5.0 μM. Complex 2e shows high potency in vitro and decreases 3D-breast cancer mammosphere viability. Mechanistic studies show 2e promotes cell death by apoptosis with plausible mode of action via endoplasmic reticulum stress induction. Tumor growth inhibition in a metastatic TNBC mouse model was observed, demonstrating 2e′s translational capability. We show for the first time the in vivo anticancer potential of a phosphine-supported tricoordinate-Au(I) complex in mice with suitable tolerability. These studies further expand the therapeutic potential of tricoordinate-Au(I) complexes.

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Expanding Three-Coordinate Gold(I) Anticancer Agent Chemical Space

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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