2-Etheny1-2,3-dihydrophthalazine-1,4-diones were successfully synthesized and proved to be effective
cytotoxic agents against the growth of suspended murine and human
leukemias and
lymphomas. Selected compounds were also active in human HeLa uterine
carcinoma, suspended effusion breast MCF-7 and
glioma HS683 screens. These agents suppressed P388
lymphocytic leukemia DNA synthesis after 60 min at 100 microM. Their target appeared to be the de novo synthesis pathway with significant inhibition of the activities of both regulatory
enzymes of the pathway, i.e. PRPP-
amide transferase and
IMP dehydrogenase resulting in a reduction in the d[NTP] pool levels for
DNA incorporation. The compounds did not affect de novo
pyrimidine synthesis and its regulatory
enzymes. Very minor reduction by the agents was noted for the
nucleoside kinases and the
DNA and
RNA polymerase activities within 60 min.
DNA was not a target of the agents in that there was no alkylation of the
nucleotide bases, intercalation between base pairs or cross-linking of the
DNA strands; however, the agents did cause P388
DNA strand scission after 24 h at 100 microM.