title: Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): a combined experimental and theoretical study.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Popović-Bijelić
authors.forename: Christian R
authors.initials: CR
authors.lastname: Kowol
authors.forename: Maria E S
authors.initials: ME
authors.lastname: Lind
authors.forename: Jinghui
authors.initials: J
authors.lastname: Luo
authors.forename: Fahmi
authors.initials: F
authors.lastname: Himo
authors.forename: Eva A
authors.initials: EA
authors.lastname: Enyedy
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D004355:Drug Stability; D005609:Free Radicals / Q000737:chemistry; D005708:Gallium / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005609:Free Radicals; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D003300:Copper; D005708:Gallium; D007501:Iron; D012264:Ribonucleotide Reductases; D015032:Zinc