A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells

Sailajah Gukathasan; Oluwatosin A. Obisesan; Setareh Saryazdi; Libby Ratliff; Sean Parkin; Robert B. Grossman; Samuel G. Awuah

doi:10.1021/acs.inorgchem.3c02066

A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells

Sailajah Gukathasan, Oluwatosin A. Obisesan, Setareh Saryazdi, Libby Ratliff, Sean Parkin, Robert B. Grossman, Samuel G. Awuah

Research output: Contribution to journal › Article › peer-review

Abstract

Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and have been leveraged for biological use. In this work, we report the synthesis and characterization of a novel class of cyclometalated [C^N] Au(III) complexes bearing secondary diamines including a norbornane backbone, (2R,3S)-N²,N³-dibenzylbicyclo[2.2.1]heptane-2,3-diamine, or a cyclohexane backbone, (1R,2R)-N¹,N²-dibenzylcyclohexane-1,2-diamine. X-ray crystallography confirms the square-planar geometry and chirality at nitrogen. The electronic character of the conformationally restricted norbornane backbone influences the electrochemical behavior with redox potentials of −0.8 to −1.1 V, atypical for Au(III) complexes. These compounds demonstrate promising anticancer activity, particularly, complex 1, which bears a benzylpyridine organogold framework, and supported by the bicyclic conformationally restricted diaminonorbornane, shows good potency in A2780 cells. We further show that a cellular response to 1 evokes reactive oxygen species (ROS) production and does not induce mitochondrial dysfunction. This class of complexes provides significant stability and reactivity for different applications in protein modification, catalysis, and therapeutics.

Original language	English
Pages (from-to)	13118-13129
Number of pages	12
Journal	Inorganic Chemistry
Volume	62
Issue number	32
DOIs	https://doi.org/10.1021/acs.inorgchem.3c02066
State	Published - Aug 14 2023

Bibliographical note

Funding Information:
We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (to S.G.A.) and a National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559). We thank the following facilities at the University of Kentucky, who provided support in completion of the experiments detailed in this paper: The UK NMR Center supported by the NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from the NSF (CHE-1625732). For the flow cytometry experiments, we thank UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). We also thank Dr. Pat Sullivan’s laboratory for access to their Seahorse XF96 and Dr. Hemendra Vekaria for running mito stress experiments.

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry

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title = "A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells",

abstract = "Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and have been leveraged for biological use. In this work, we report the synthesis and characterization of a novel class of cyclometalated [C^N] Au(III) complexes bearing secondary diamines including a norbornane backbone, (2R,3S)-N2,N3-dibenzylbicyclo[2.2.1]heptane-2,3-diamine, or a cyclohexane backbone, (1R,2R)-N1,N2-dibenzylcyclohexane-1,2-diamine. X-ray crystallography confirms the square-planar geometry and chirality at nitrogen. The electronic character of the conformationally restricted norbornane backbone influences the electrochemical behavior with redox potentials of −0.8 to −1.1 V, atypical for Au(III) complexes. These compounds demonstrate promising anticancer activity, particularly, complex 1, which bears a benzylpyridine organogold framework, and supported by the bicyclic conformationally restricted diaminonorbornane, shows good potency in A2780 cells. We further show that a cellular response to 1 evokes reactive oxygen species (ROS) production and does not induce mitochondrial dysfunction. This class of complexes provides significant stability and reactivity for different applications in protein modification, catalysis, and therapeutics.",

author = "Sailajah Gukathasan and Obisesan, {Oluwatosin A.} and Setareh Saryazdi and Libby Ratliff and Sean Parkin and Grossman, {Robert B.} and Awuah, {Samuel G.}",

note = "Funding Information: We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (to S.G.A.) and a National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559). We thank the following facilities at the University of Kentucky, who provided support in completion of the experiments detailed in this paper: The UK NMR Center supported by the NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from the NSF (CHE-1625732). For the flow cytometry experiments, we thank UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). We also thank Dr. Pat Sullivan{\textquoteright}s laboratory for access to their Seahorse XF96 and Dr. Hemendra Vekaria for running mito stress experiments. Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

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AU - Ratliff, Libby

AU - Parkin, Sean

AU - Grossman, Robert B.

AU - Awuah, Samuel G.

N1 - Funding Information: We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (to S.G.A.) and a National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559). We thank the following facilities at the University of Kentucky, who provided support in completion of the experiments detailed in this paper: The UK NMR Center supported by the NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from the NSF (CHE-1625732). For the flow cytometry experiments, we thank UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). We also thank Dr. Pat Sullivan’s laboratory for access to their Seahorse XF96 and Dr. Hemendra Vekaria for running mito stress experiments. Publisher Copyright: © 2023 American Chemical Society.

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A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells

Abstract

Bibliographical note

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