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ACS Med Chem Lett. 2017 Sep 6;8(10):997-1001. doi: 10.1021/acsmedchemlett.7b00162. eCollection 2017.

Auranofin, Et3PAuCl, and Et3PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study.

Author information

  • 1Department of Chemistry and Industrial Chemistry (DCCI), University of Pisa, Via Moruzzi, 13, 56124 Pisa, Italy.
  • 2Laboratory of Metals in Medicine (MetMed), Department of Chemistry "U. Schiff", University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
  • 3Department of Biochemical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
  • 4DI.V.A.L Toscana S.R.L., Via Madonna del Piano, 6, 50019 Sesto Fiorentino, Italy.
  • 5Department of Experimental and Clinical Medicine, University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.

Abstract

The solution behavior of auranofin, Et3PAuCl  and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity experiments for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et3PAuI and Et3PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacological action, suggesting that the tuning of some relevant chemical properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacological effects.

KEYWORDS:

Auranofin; DNA interaction; anticancer drugs; colorectal cancer; in vivo experiments; protein interaction; thioredoxin reductase

PMID:
29057040
PMCID:
PMC5641946
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00162
[PubMed]
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