Cytotoxicity of 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and mode of action in human Tmolt(4) cells

The 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and thei r copper complexes demonstrated potent cytotoxic activity against a series of murine and human suspended cultured tumor cells. Selected compounds were active against the growth of cultured cells from solid human tumors, i.e. Mck-7 breast effusion, lung A549 and lung MB-9812, bone SOS-2 and clear cel l Caki renal tumor. In Tmolt(4) T cell leukemia cells the compounds inhibit ed the syntheses of DNA, RNA and protein over 60 min at 25 to 100 muM. Mult iple target sites in nucleic acid metabolism were suppressed by the agents, i.e. DNA polymerase a, ribonucleoside reductase, dihydrofolate reductase, de novo purine synthesis, thymidylate synthetase and nucleoside kinases. Th e total effects of the agents on DNA metabolism led to the reduction of deo xyribonucleotide pools as well as DNA fragmentation.