Exploring six-coordinate germanium(IV)-diketonate complexes as anticancer agents

Randall T. Mertens; Sean Parkin; Samuel G. Awuah

doi:10.1016/j.ica.2019.119375

Exploring six-coordinate germanium(IV)-diketonate complexes as anticancer agents

Randall T. Mertens, Sean Parkin, Samuel G. Awuah

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

7 Scopus citations

Abstract

Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [Ge^IV(acac)₃)]⁺, with different anions (3 – 6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3–5 revealed distinct irreversible peaks in the range of −0.9 to −1.9 V, corresponding to Ge(IV)/Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC₅₀ values in the sub-micromolar range (9–15 μΜ). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.

Original language	English
Article number	119375
Journal	Inorganica Chimica Acta
Volume	503
DOIs	https://doi.org/10.1016/j.ica.2019.119375
State	Published - Apr 1 2020

Bibliographical note

Funding Information:
We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF ( CHE-997738 ) and the UK X-ray facility supported by the MRI program from NSF ( CHE-1625732 ). We would like to also thank Greg Bauman Ph.D (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 ) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen’s laboratory (UK College of Pharmacy ) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia). Appendix A

Funding Information:
We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). We would like to also thank Greg Bauman Ph.D (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) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia).

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

Anticancer
Cytotoxicity
Drug discovery
Germanium
Metalloid
Resistance

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry
Materials Chemistry

UN SDGs

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

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10.1016/j.ica.2019.119375

Cite this

@article{b12a009eeb2a44d397ae3e7b9a109216,

title = "Exploring six-coordinate germanium(IV)-diketonate complexes as anticancer agents",

abstract = "Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [GeIV(acac)3)]+, with different anions (3 – 6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3–5 revealed distinct irreversible peaks in the range of −0.9 to −1.9 V, corresponding to Ge(IV)/Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC50 values in the sub-micromolar range (9–15 μΜ). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.",

keywords = "Anticancer, Cytotoxicity, Drug discovery, Germanium, Metalloid, Resistance",

author = "Mertens, {Randall T.} and Sean Parkin and Awuah, {Samuel G.}",

note = "Funding Information: We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF ( CHE-997738 ) and the UK X-ray facility supported by the MRI program from NSF ( CHE-1625732 ). We would like to also thank Greg Bauman Ph.D (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 ) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen{\textquoteright}s laboratory (UK College of Pharmacy ) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia). Appendix A Funding Information: We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). We would like to also thank Greg Bauman Ph.D (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) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia). Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

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doi = "10.1016/j.ica.2019.119375",

language = "English",

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AU - Mertens, Randall T.

AU - Parkin, Sean

AU - Awuah, Samuel G.

N1 - Funding Information: We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF ( CHE-997738 ) and the UK X-ray facility supported by the MRI program from NSF ( CHE-1625732 ). We would like to also thank Greg Bauman Ph.D (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 ) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen’s laboratory (UK College of Pharmacy ) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia). Appendix A Funding Information: We thank the University of Kentucky for start-up funding. We are very grateful for the facilities and staff at the University of Kentucky who supported the work presented in this manuscript. We would like to thank the UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). We would like to also thank Greg Bauman Ph.D (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) as well as Thomas Wilkop Ph.D and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We are grateful for the use of Dr. Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS. Elemental analysis was performed with the help of Atlantic Microlabs, Inc (Atlanta, Georgia). Publisher Copyright: © 2019 Elsevier B.V.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [GeIV(acac)3)]+, with different anions (3 – 6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3–5 revealed distinct irreversible peaks in the range of −0.9 to −1.9 V, corresponding to Ge(IV)/Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC50 values in the sub-micromolar range (9–15 μΜ). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.

AB - Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [GeIV(acac)3)]+, with different anions (3 – 6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3–5 revealed distinct irreversible peaks in the range of −0.9 to −1.9 V, corresponding to Ge(IV)/Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC50 values in the sub-micromolar range (9–15 μΜ). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.

KW - Anticancer

KW - Cytotoxicity

KW - Drug discovery

KW - Germanium

KW - Metalloid

KW - Resistance

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Exploring six-coordinate germanium(IV)-diketonate complexes as anticancer agents

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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