EFFECTS OF METAL(III) COORDINATION ON BIOLOGICAL ACTIVITY OF 2,2'-BIPYRIDYL-6-CARBOTHIOAMIDE (BPYTA), A POTENT R2 RIBONUCLEOTIDE REDUCTASE INHIBITOR

Investigations from our laboratory have led to the development of 2,2'-bipyridyl-6-carbothioamide (BPYTA), that demonstrated a powerful cytotoxicity for rodent and human tumoral cell lines and for peripheral blasts from patients suffering from acute leukemia.1 The BPYTA cytotoxic effect is mainly due to the inhibition of ribonucleotide reductase (RR), the enzyme responsible for reductive conversion of ribo- to deoxyribonucleotides that has long been regarded as an important target for therapies aiming to control pathologies that depend strongly on DNA replication. BPYTA is characterized by chelating properties because of the N*-N*-S* tridentate coordination system similar to that of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones, whose metal complexes have been extensively investigated. However, the properties of BPYTA-complexes and thiosemicarbazone-complexes are not identical. Among the transition-metal(II) complexes with BPYTA, the iron chelate [BPYTA-Fe(II), molar ratio 2:1], is the active form of the ligand which destroys the tyrosyl radical of RR small subunit R2, while other transition-metal complexes resulted in significant differences in biochemical effects of the ligand and, perhaps, also for its mechanism of action.2 In the present study we report on the effects of metal(III) coordination on the pharmacological properties of BPYTA. In particular, new complexes with gallium(III) and iron(III) with the general formula [M(L)2]+ have been prepared and investigated for their biological activity. Moreover, a novel improved and inexpensive synthesis of BPYTA has been developed. References 1-NOCENTINI, G., et al., 1993. 2,2'-Bipyridyl-6-carbothioamide and its ferrous complex: their in vitro antitumoral activity related to the inhibition of ribonucleotide reductase R2 subunit. Cancer Research, 53, 19-26. 2-FRANCHETTI, P., et al., 1988. Metal(II) complexes of 2,2'-bipyridyl-6-carbothioamide as antitumor and antifungal agents. European Journal of Medicinal Chemistry, 23, 301-305.