Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent

Denana Miodragović, Antonello Merlino*, Elden P. Swindell, Abraham Bogachkov, Richard W. Ahn, Sara Abuhadba, Giarita Ferraro, Tiziano Marzo, Andrew P. Mazar, Luigi Messori, Thomas V O'Halloran

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules - proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nμ of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.

Original languageEnglish (US)
Pages (from-to)6453-6457
Number of pages5
JournalJournal of the American Chemical Society
Volume141
Issue number16
DOIs
StatePublished - Apr 24 2019

Fingerprint

Antineoplastic Agents
DNA
Arsenic
Cisplatin
Tumors
Cells
Proteins
Neoplasms
Biomolecules
Platinum
Pharmaceutical Preparations
Blood
Tumor Cell Line
Acids
Cell Line
arsenic trioxide
hydroxide ion
arsenous acid

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Miodragović, D., Merlino, A., Swindell, E. P., Bogachkov, A., Ahn, R. W., Abuhadba, S., ... O'Halloran, T. V. (2019). Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent. Journal of the American Chemical Society, 141(16), 6453-6457. https://doi.org/10.1021/jacs.8b13681
Miodragović, Denana ; Merlino, Antonello ; Swindell, Elden P. ; Bogachkov, Abraham ; Ahn, Richard W. ; Abuhadba, Sara ; Ferraro, Giarita ; Marzo, Tiziano ; Mazar, Andrew P. ; Messori, Luigi ; O'Halloran, Thomas V. / Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 16. pp. 6453-6457.
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Miodragović, D, Merlino, A, Swindell, EP, Bogachkov, A, Ahn, RW, Abuhadba, S, Ferraro, G, Marzo, T, Mazar, AP, Messori, L & O'Halloran, TV 2019, 'Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent', Journal of the American Chemical Society, vol. 141, no. 16, pp. 6453-6457. https://doi.org/10.1021/jacs.8b13681

Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent. / Miodragović, Denana; Merlino, Antonello; Swindell, Elden P.; Bogachkov, Abraham; Ahn, Richard W.; Abuhadba, Sara; Ferraro, Giarita; Marzo, Tiziano; Mazar, Andrew P.; Messori, Luigi; O'Halloran, Thomas V.

In: Journal of the American Chemical Society, Vol. 141, No. 16, 24.04.2019, p. 6453-6457.

Research output: Contribution to journalArticle

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AU - Miodragović, Denana

AU - Merlino, Antonello

AU - Swindell, Elden P.

AU - Bogachkov, Abraham

AU - Ahn, Richard W.

AU - Abuhadba, Sara

AU - Ferraro, Giarita

AU - Marzo, Tiziano

AU - Mazar, Andrew P.

AU - Messori, Luigi

AU - O'Halloran, Thomas V

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N2 - Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules - proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nμ of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.

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Miodragović D, Merlino A, Swindell EP, Bogachkov A, Ahn RW, Abuhadba S et al. Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent. Journal of the American Chemical Society. 2019 Apr 24;141(16):6453-6457. https://doi.org/10.1021/jacs.8b13681