Several alpha-N-heterocyclic carboxaldehyde thiosemicarbazones and their iron and copper complexes have been tested for their cytotoxicity and inhibiting activity against DNA synthesis under controlled metal conditions. No ligands show cytotoxicity against Ehrlich cells at the concentrations tested, while some iron and copper complexes are active. In contrast, the ligands inhibit DNA synthesis at much lower concentrations than used above. Similarly, the metal complexes are effective inhibitors at concentrations much below those necessary to demonstrate cytotoxicity. In addition, the iron complexes of 1-formylisoquinoline thiosemicarbazone, 2-formylpyridine thiosemicarbazone, and 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone were shown to be three- to sixfold more active than their free ligands as inhibitors of partially purified ribonucleotide reductase to which no iron has been added. The copper complex of 2-formylpyridine thiosemicarbazone was slightly more active than the free ligand against the reductase.

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This study examines the concentration-dependent cytotoxicity and antitumor activity of bleomycin (Blm) and Cu-, Zn-, Fe(III)-, and CoBlm using Ehrlich cells in culture and the Ehrlich ascites tumor. The order of activity in culture under several conditions is CuBlm approximately equal to Blm approximately equal to ZnBlm > Fe(III)Blm > CoBlm approximately equal to control. Short exposures of cells to drugs in the presence or absence of serum produced effects on cell proliferation similar to 48-h incubations. With Blm and CuBlm there was no obvious relationship between cytotoxicity and the modest short-term inhibition of DNA synthesis by the drugs. The antitumor experiments produced qualitatively similar results with the order of antitumor potency being CuBlm > Blm > ZnBlm approximately equal to FeBlm > CoBlm approximately equal to control tumor. The host toxicity produced by these drugs as measured by weight loss had the opposite ordering: CoBlm < FeBlm < ZnBlm < Blm < CuBlm. At therapeutically effective concentrations, FeFlm was significantly less toxic relative to ther other active agents.

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