The 1-(1-phenylalkylideneamino)-2,4-azetidinediones are potent
cytotoxic agents against the growth of human and murine
leukemias,
lymphoma, and suspended HeLa uterine
carcinoma. In cell lines cultured from solid human
tumors, the agents were more selective with only a few agents demonstrating significant activity against the growth of HCT-8 ileum
adenocarcinoma, Saos-2
osteosarcoma, KB nasopharynx, MCF-7 breast effusion, and ovary 1-A9
carcinoma A mode of action study in murine L1210
lymphoid leukemia cells showed that the agents inhibited
DNA and
RNA syntheses after 60 min. The compounds were potent inhibitors of the de novo
purine synthesis suppressing the activity of both regulatory
enzymes of the pathway, i.e., PRPP-amido
transferase and
IMP dehydrogenase. In addition, the agents reduced the activity of
ribonucleotide reductase,
dihydrofolate reductase,
RNA polymerases, and
thymidine kinases as well as the reduction of d[NTP] pools. All of these effects would contribute to the overall reduction of
DNA and
RNA syntheses. The
DNA molecule itself was not a target for the agents in that alkylation of nucleoide bases, intercalation between base pairs, and cross-linking of
DNA strands did not occur.