1 Chemical and Biological Properties of Cytotoxic α-(N)-Heterocyclic Carboxaldehyde Thiosemicarbazones

This chapter discusses chemical and biological properties of cytotoxic α-(N)-heterocyclic carboxaldehyde. Ribonucleoside diphosphate reductase is a critical enzyme in the de novo synthesis of the deoxyribonucleotide precursors of DNA and, as such, is essential for cellular replication. Thus, its presence and activity is closely correlated with cellular growth rates. It seems reasonable that a strong inhibitor of ribonucleoside diphosphate reductase would be a useful weapon in the therapeutic armamentarium against cancer. Several different classes of agents are relatively specific inhibitors of ribonucleoside diphosphate reductase. These have included α-(N)-heterocyclic carboxaldehyde thiosemicarbazones (HCTs), hydroxyurea, N-hydroxy-N´-aminoguanidine derivatives and polyhydroxybenzohydroxamates. The HCTs, as a class, are among the most potent known inhibitors of ribonucleoside diphosphate reductase, being 80-5000 times more effective, depending upon the HCT, than hydroxyurea, a clinically useful anticancer agent. The primary metabolic lesion created by the HCTs is interference with the biosynthesis of DNA, an action resulting from the potent inhibition of ribonucleotide reductase activity.