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Understanding the metabolism of the anticancer drug Triapine: electrochemical oxidation, microsomal incubations and in vivo analysis using LC-HRMS

Abstract

α-N-heterocyclic thiosemicarbazones belong to the most promising ribonucleotide reductase inhibitors identified so far. Triapine, the most prominent representative among the substance class, has been investigated in multiple phase I and II clinical trials. With regard to the clinical practice, Triapine showed activity against hematological diseases, but ineffectiveness against a variety of solid tumors. However, the reasons are still vague and the ADME (adsorption, distribution, metabolism and excretion) data of Triapine available in literature are very limited. Therefore, different analytical tools were used to investigate the metabolism of Triapine including electrochemical oxidations, liver microsomes and in vivo samples from mice. The main metabolic reactions, observed by all three methods, were dehydrogenation and hydroxylations, confirming that electrochemistry, as the purely instrumental approach, can be applied for simulation of metabolic pathways. The dehydrogenated metabolite M1 was identified as a thiadiazole ring-closed oxidation product of Triapine. From the biological point of view, M1, as a key metabolite, is of interest since the crucial chemical property of α-N-heterocyclic thiosemicarbazones to bind metal ions is lost and cytotoxicity studies showed no anticancer activity. The in vivo data of the urine samples revealed very high levels of the metabolites and Triapine itself already 15 min after treatment. This clearly indicated that Triapine is rapidly metabolised and excreted, which represents an important step forward to understand the possible explanation for the inefficiency of Triapine against solid tumors.

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Publication details

The article was received on 01 Jun 2017, accepted on 07 Jul 2017 and first published on 07 Jul 2017


Article type: Paper
DOI: 10.1039/C7AN00902J
Citation: Analyst, 2017, Accepted Manuscript
  • Open access: Creative Commons BY license
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    Understanding the metabolism of the anticancer drug Triapine: electrochemical oxidation, microsomal incubations and in vivo analysis using LC-HRMS

    K. Pelivan, L. Frensemeier, U. Karst, G. Koellensperger, B. Bielec, S. Hager, P. Heffeter, B. K. Keppler and C. R. Kowol, Analyst, 2017, Accepted Manuscript , DOI: 10.1039/C7AN00902J

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