Cyclometalated Gold(III) Complexes Bearing DACH Ligands

Sailajah Gukathasan; Sean Parkin; Samuel G. Awuah

doi:10.1021/acs.inorgchem.9b01031

Cyclometalated Gold(III) Complexes Bearing DACH Ligands

Sailajah Gukathasan, Sean Parkin, Samuel G. Awuah

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

34 Scopus citations

Abstract

The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C-N)Cl₂] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)₂]⁺ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]²⁺. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC₅₀ in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex 5 does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.

Original language	English
Pages (from-to)	9326-9340
Number of pages	15
Journal	Inorganic Chemistry
Volume	58
Issue number	14
DOIs	https://doi.org/10.1021/acs.inorgchem.9b01031
State	Published - Jul 15 2019

Bibliographical note

Funding Information:
*E-mail: awuah@uky.edu. ORCID Samuel G. Awuah: 0000-0003-4947-7283 Funding We are grateful to the University of Kentucky for start-up funding and UK Igniting Research Collaboration (IRC) for financial assistance. Notes The authors declare no competing financial interest.

Funding Information:
We are grateful for the staff and facilities at the University of Kentucky that supported this work. This study made use of an NMR facility supported by NSF (CHE-9977388) as well as the UK X-ray facility with funds from the MRI program of the National Science Foundation (Grants CHE-0319176 and CHE-1625732) and Environmental Research Training Laboratory (ERTL) for their assistance with ICP - OES. UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Thanks to the staff of CIC, Boston University, for running mass spectrometry samples. Thanks to the microanalysis laboratory at the University of Illinois at Urbana−Champaign for elemental analysis (CHN). We are grateful to the UK HPC for providing high performance computing facilities and useful technical support as well as to Harsha Attanayake (Dr. Susan Odom’s lab) for electrochemistry discussion and to Samuel Ofori for assistance in tissue culture experiments.

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry

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title = "Cyclometalated Gold(III) Complexes Bearing DACH Ligands",

abstract = "The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C-N)Cl2] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)2]+ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]2+. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC50 in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex 5 does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.",

author = "Sailajah Gukathasan and Sean Parkin and Awuah, {Samuel G.}",

note = "Funding Information: *E-mail: awuah@uky.edu. ORCID Samuel G. Awuah: 0000-0003-4947-7283 Funding We are grateful to the University of Kentucky for start-up funding and UK Igniting Research Collaboration (IRC) for financial assistance. Notes The authors declare no competing financial interest. Funding Information: We are grateful for the staff and facilities at the University of Kentucky that supported this work. This study made use of an NMR facility supported by NSF (CHE-9977388) as well as the UK X-ray facility with funds from the MRI program of the National Science Foundation (Grants CHE-0319176 and CHE-1625732) and Environmental Research Training Laboratory (ERTL) for their assistance with ICP - OES. UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Thanks to the staff of CIC, Boston University, for running mass spectrometry samples. Thanks to the microanalysis laboratory at the University of Illinois at Urbana−Champaign for elemental analysis (CHN). We are grateful to the UK HPC for providing high performance computing facilities and useful technical support as well as to Harsha Attanayake (Dr. Susan Odom{\textquoteright}s lab) for electrochemistry discussion and to Samuel Ofori for assistance in tissue culture experiments. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

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N1 - Funding Information: *E-mail: awuah@uky.edu. ORCID Samuel G. Awuah: 0000-0003-4947-7283 Funding We are grateful to the University of Kentucky for start-up funding and UK Igniting Research Collaboration (IRC) for financial assistance. Notes The authors declare no competing financial interest. Funding Information: We are grateful for the staff and facilities at the University of Kentucky that supported this work. This study made use of an NMR facility supported by NSF (CHE-9977388) as well as the UK X-ray facility with funds from the MRI program of the National Science Foundation (Grants CHE-0319176 and CHE-1625732) and Environmental Research Training Laboratory (ERTL) for their assistance with ICP - OES. UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Thanks to the staff of CIC, Boston University, for running mass spectrometry samples. Thanks to the microanalysis laboratory at the University of Illinois at Urbana−Champaign for elemental analysis (CHN). We are grateful to the UK HPC for providing high performance computing facilities and useful technical support as well as to Harsha Attanayake (Dr. Susan Odom’s lab) for electrochemistry discussion and to Samuel Ofori for assistance in tissue culture experiments. Publisher Copyright: © 2019 American Chemical Society.

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N2 - The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C-N)Cl2] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)2]+ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]2+. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC50 in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex 5 does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.

AB - The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C-N)Cl2] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)2]+ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]2+. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC50 in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex 5 does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.

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Cyclometalated Gold(III) Complexes Bearing DACH Ligands

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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