Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): A combined experimental and theoretical study

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Popović-Bijelić, Ana,1976-Stockholms universitet,Institutionen för biokemi och biofysik (author)

Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) : A combined experimental and theoretical study

Article/chapterEnglish2011

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Elsevier,2011
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LIBRIS-ID:oai:DiVA.org:su-69327
https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-69327URI
https://doi.org/10.1016/j.jinorgbio.2011.07.003DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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8
Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is currently the most promising chemotherapeutic compound among the class of α-N-heterocyclic thiosemicarbazones. Here we report further insights into the mechanism(s) of anticancer drug activity and inhibition of mouse ribonucleotide reductase (RNR) by Triapine. In addition to the metal-free ligand, its iron(III), gallium(III), zinc(II) and copper(II) complexes were studied, aiming to correlate their cytotoxic activities with their effects on the diferric/tyrosyl radical center of the RNR enzyme in vitro. In this study we propose for the first time a potential specific binding pocket for Triapine on the surface of the mouse R2 RNR protein. In our mechanistic model, interaction with Triapine results in the labilization of the diferric center in the R2 protein. Subsequently the Triapine molecules act as iron chelators. In the absence of external reductants, and in presence of the mouse R2 RNR protein, catalytic amounts of the iron(III)–Triapine are reduced to the iron(II)–Triapine complex. In the presence of an external reductant (dithiothreitol), stoichiometric amounts of the potently reactive iron(II)–Triapine complex are formed. Formation of the iron(II)–Triapine complex, as the essential part of the reaction outcome, promotes further reactions with molecular oxygen, which give rise to reactive oxygen species (ROS) and thereby damage the RNR enzyme. Triapine affects the diferric center of the mouse R2 protein and, unlike hydroxyurea, is not a potent reductant, not likely to act directly on the tyrosyl radical.

Subject headings and genre

NATURVETENSKAP Kemi Organisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Organic Chemistry hsv//eng
NATURVETENSKAP Biologi Biofysik hsv//swe
NATURAL SCIENCES Biological Sciences Biophysics hsv//eng
Ribonucleotide reductase (RNR)
Triapine
Tyrosyl radical
Metal complex
Cytotoxicity
EPR
Biophysics
biofysik

Added entries (persons, corporate bodies, meetings, titles ...)

Kowol, Christian R. (author)
Lind, Maria E. S.Stockholms universitet,Institutionen för organisk kemi(Swepub:su)mali6341 (author)
Luo, JinghuiStockholms universitet,Institutionen för biokemi och biofysik (author)
Himo, FahmiStockholms universitet,Institutionen för organisk kemi(Swepub:su)himo (author)
Enyedy, Éva A. (author)
Arion, Vladimir B. (author)
Gräslund, AstridStockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)astrid (author)
Stockholms universitetInstitutionen för biokemi och biofysik (creator_code:org_t)

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In:European Journal of Inorganic Chemistry: Elsevier105:11, s. 1422-14311434-19481099-19480162-0134

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