CYTOTOXICITY OF IMIDES-N-ALKYL SEMICARBAZONES, THIOSEMICARBAZANES, ACETYLHYDRAZONES AND RELATED DERIVATIVES

The semicarbazones, thiosemicarbazones and acetyl-hydrazones of phthal imide, o-benzosulfimide, naphthalimide and diphenimide demonstrated po tent cytotoxicity against murine and human leukemia cell growth and cu ltured cell growth from human solid tumors. The major site of inhibiti on in L1210 leukemia cells was DNA synthesis after 60 min incubated wi th the agents at 25, 50 and 100 mu M. De novo synthesis of purines at the regulatory enzyme sites of PRPP amidotransferase and IMP dehydroge nase were the major targets of the agent. Thymidylate synthetase, dihy drofolate reductase and ribonucleoside reductase activities were inhib ited by the agents in a manner which would contribute to the overall r eduction of DNA synthesis and cell death. d(NTP) pools were significan tly reduced and the evidence suggests that the agents interacted with DNA affording DNA strand scission which would interfere with both temp late utilization by the polymerases and also ultimately reduce nucleic acid synthesis.