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Monofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique?

  • Christine E. McDevitt
  • Matthew V. Yglesias
  • Austin M. Mroz
  • Emily C. Sutton
  • Min Chieh Yang
  • Christopher H. Hendon
  • Victoria J. DeRoseEmail author
Original Paper
Part of the following topical collections:
  1. Joan Broderick: Papers in Celebration of Her 2019 ACS Alfred Bader Award in Bioinorganic or Bioorganic Chemistry

Abstract

Platinum anticancer therapeutics are widely used in a variety of chemotherapy regimens. Recent work has revealed that the cytotoxicity of oxaliplatin and phenanthriplatin is through induction of ribosome biogenesis stress pathways, differentiating them from cisplatin and other compounds that mainly work through DNA damage response mechanisms. To probe the structure–activity relationships in phenanthriplatin’s ability to cause nucleolar stress, a series of monofunctional platinum(II) compounds differing in ring number, size and orientation was tested by nucleophosmin (NPM1) relocalization assays using A549 cells. Phenanthriplatin was found to be unique among these compounds in inducing NPM1 relocalization. To decipher underlying reasons, computational predictions of steric bulk, platinum(II) compound surface length and hydrophobicity were performed for all compounds. Of the monofunctional platinum(II) compounds tested, phenanthriplatin has the highest calculated hydrophobicity and volume but does not exhibit the largest distance from platinum(II) to the surface. Thus, spatial orientation and/or hydrophobicity caused by the presence of a third aromatic ring may be significant factors in the ability of phenanthriplatin to cause nucleolar stress.

Graphic abstract

Keywords

Platinum Anticancer drug Cell death Structure–activity relationship Computational chemistry Imaging Nucleolus 

Notes

Acknowledgements

This work was supported by the National Science Foundation [CHE1710721 to VJD], the NIH [T32 GM007759-29 to ECS] and used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation [ACI-1548562]. Computations were also performed on the PICS Coeus high performance computer, which is supported by the National Science Foundation [1624776]. This work is also supported by the Department of Chemistry and Biochemistry, Department of Biology, Institute of Molecular Biology and the Material Science Institute at the University of Oregon.

Author contributions

CEM: conceptualization, investigation, validation, writing original draft, visualization, and supervision. MVY: software, investigation, formal analysis, data curation, writing review and editing, and visualization. AMM: methodology, software, formal analysis, data curation, writing review and editing, and visualization. ECS: conceptualization, methodology, data curation, writing review and editing. MY: software, investigation, data curation, writing review and editing. CHH: project administration, funding acquisition, writing review and editing. VJD: project administration, funding acquisition, writing review and editing.

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Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Christine E. McDevitt
    • 1
  • Matthew V. Yglesias
    • 1
    • 2
  • Austin M. Mroz
    • 1
    • 3
  • Emily C. Sutton
    • 2
    • 4
  • Min Chieh Yang
    • 1
    • 3
  • Christopher H. Hendon
    • 1
    • 3
  • Victoria J. DeRose
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Chemistry and Biochemistry1253 University of OregonEugeneUSA
  2. 2.Institute of Molecular Biology1229 University of OregonEugeneUSA
  3. 3.Materials Science Institute1252 University of OregonEugeneUSA
  4. 4.Department of Biology1210 University of OregonEugeneUSA

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