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Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): A combined experimental and theoretical study
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Vise andre og tillknytning
2011 (engelsk)Inngår i: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, Vol. 105, nr 11, s. 1422-1431Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
Elsevier, 2011. Vol. 105, nr 11, s. 1422-1431
Emneord [en]
Ribonucleotide reductase (RNR), Triapine, Tyrosyl radical, Metal complex, Cytotoxicity, EPR
HSV kategori
Forskningsprogram
biofysik
Identifikatorer
URN: urn:nbn:se:su:diva-69327DOI: 10.1016/j.jinorgbio.2011.07.003ISI: 000297565500008OAI: oai:DiVA.org:su-69327DiVA, id: diva2:476086
Forskningsfinansiär
Swedish Research Council
Merknad
8Tilgjengelig fra: 2012-01-11 Laget: 2012-01-11 Sist oppdatert: 2017-12-08bibliografisk kontrollert
Inngår i avhandling
1. Activation and inhibition of diiron and iron-manganese ribonucleotide reductases
Åpne denne publikasjonen i ny fane eller vindu >>Activation and inhibition of diiron and iron-manganese ribonucleotide reductases
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Ribonucleotide reductase (RNR) catalyses the reduction of ribonucleotides to deoxyribonucleotides. In conventional class I RNRs the active site is located in the R1 subunit, and the R2 subunit contains a diiron cofactor and a stable tyrosyl radical essential for activity.

Class Ic Chlamydia trachomatis RNR lacks the tyrosyl radical and uses a Mn(IV)Fe(III) cofactor for catalysis. The requirement for metals for RNR activation was studied in C. trachomatis F127Y and Y129F R2, and in mouse wild type and Y177F R2 proteins. The results indicate that R2 affinity for metals is determined by the amino acid located next to the metal site, at the position of the radical carrying tyrosyl. Specifically, R2 proteins that contain phenylalanine in this place bind Mn and Fe, and the tyrosyl containing R2s bind only Fe.

Further results show that C. trachomatis RNR can be inhibited by R2 C-terminal oligopeptides. The highest inhibition was observed for a 20-mer peptide indicating that the oligopeptide inhibition mechanism of class Ic is similar to that of the class Ia and b.

The second part of the thesis deals with class Ia RNR inhibition. The results show that a lanthanum complex containing three 1,10-phenantroline molecules (KP772) which has showed promising cytotoxic activity in cancer cell lines inhibits mouse R2 protein in the presence of external reductants by iron-chelation. It is suggested that KP772 has several synergistic inhibition mechanisms that contribute to its overall anticancer activity. Moreover, other results show that Triapine, a promising chemotherapeutic compound, and its Fe, Ga, Zn, and Cu complexes, inhibit mouse R2 in both reducing and non-reducing conditions. Inhibition by Triapine involves the binding of the drug to the surface of the R2 protein leading to labilization of the Fe-center and subsequent Fe-chelation by Triapine. Formation of the Fe(II)-Triapine complex which reacts with O2 to produce reactive oxygen species results in complete RNR inactivation.

sted, utgiver, år, opplag, sider
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2012. s. 64
Emneord
class Ic, C. trachomatis, cytotoxicity, KP772, lanthanum, manganese–iron cofactor, metal complex, oligopeptide inhibitor, ribonucleotide reductase, Triapine, tyrosyl radical
HSV kategori
Forskningsprogram
biofysik
Identifikatorer
urn:nbn:se:su:diva-75175 (URN)978-91-7447-499-2 (ISBN)
Disputas
2012-05-31, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2012-05-09 Laget: 2012-04-11 Sist oppdatert: 2012-04-16bibliografisk kontrollert

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