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2,2'-Bipyridyl-6-carbothioamide and Its Ferrous Complex: Their in Vitro Antitumoral Activity Related to the Inhibition of Ribonucleotide Reductase R2 Subunit¹

Institute of Medical Pharmacology, University of Perugia, Perugia [G. N., F. F., A. B.], and Department of Chemical Sciences, University of Camerino, Camerino [P. F.], Italy

2,2'-Bipyridyl-6-carbothioamide (BPYTA), a synthetic compound with antitumoral activity, is characterized by chelating properties because of the N*-N*-S* tridentate ligand system and is therefore comparable to -(N)-heterocyclic carboxaldehyde thiosmicarbazones which are potent inhibitors of ribonucleotide reductase (RR).

Electron paramagnetic resonance studies on the small subunit of mouse recombinant RR (R2) demonstrated that BPYTA can destroy the R2 tyrosyl radical only if Fe(II) is present (73% destruction at 50 µM, after 20 min of contact). The R2 inhibition was reversible and time dependent. Studies on tumoral lines confirmed that the main cell target of BPYTA is RR and demonstrated that the iron-complexed form compared to the nonchelated form has some difficulty in crossing the cell membrane. Spectrophotometric and electron paramagnetic resonance studies clearly indicated that BPYTA chelates iron only when this is reduced and that the BPYTA-Fe(II) complex is stable in the presence of oxygen.

From reported results we conclude that BPYTA is a powerful RR inhibitor (R2 subunit) which has a different mechanism of action from that of Desferal. It has some properties in common with -(N)-heterocyclic carboxaldehyde thiosemicarbazones, but they are not identical. It would be interesting to do further studies on the BPYTA mechanism of action and evaluate the in vivo antitumoral activity of the preformed complex.

¹ Supported in part by MURST 40%.

² To whom requests for reprints should be addressed, at Istituto di Farmacologia Medica, Università di Perugia, Via del Giochetto, 06122 Perugia, Italy.

Received 4/20/92. Accepted 10/21/92.

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