Comparative studies of the antineoplastic activity of 5-hydroxy-2-formylpyridine thiosemicarbazone and its seleno- semicarbazone, guanylhydrazone and semicarbazone analogs

Abstract

Several analogs of 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP) that contain isosteric replacement of sulfur by Se, NH or O have been synthesized. Measurement of the antineoplastic activity of these compounds in mice bearing Sarcoma 180 ascites cells indicated that 5-HP was the most active of these agents; the seleno analog was intermediate in potency, and the guanylhydrazone and semicarbazone were inactive against this tumor. 5-HP and its seleno analog both caused marked inhibition of DNA synthesis in vitro, as measured by the incorporation of thymidine-methyl- 3H, 5- 3H-cytidine or adenine-8- 14C into DNA. The syntheses of RNA and protein were relatively unaffected by these agents under the conditions employed. None of the compounds prevented the incorporation of 5- 3H-cytidine into acid-soluble pyrimidine ribonucleotides, but 5-HP and its selenosemicarbazone markedly depressed the subsequent progression of radioactivity into pyrimidine deoxyribonucleotide pools, suggesting that these two derivatives inhibited the enzyme ribonucleoside diphosphate reductase in situ. Both 5-HP and the seleno analog inhibited the isolated enzyme ribonucleoside diphosphate reductase from the Novikoff rat hepatoma; to achieve 50 per cent inhibition required 3.5 × 10 −6 and 6.8 × 10 −6 M respectively. Metal/ ligand ratios and the association constants for these ligands with cobalt and copper were determined. The cobalt/ligand ratio for 5-HP and its seleno analog was 1:2 and the copper/ ligand ratio for these agents was 1:1. Metal/ligand ratios for the guanylhydrazone and semicarbazone derivatives were 1:3 for cobalt and 1:2 for copper. Association constants for 5-HP and the seleno derivative with cobalt were 56 × 10 9 and 7.6 × 10 9 respectively. The findings demonstrated that 5-HP was the optimum member of this series with respect to antineoplastic potency and that tumor-inhibitory activity correlated with the degree of inhibition of the synthesis of DNA and the capacity for metal binding.