Cytotoxicity of 2-ethenyl-2,3-dihydrophthalazine-1,4-diones in murine and human tumor cultured cells

2-Ethenyl-2.3-dihydrophthalazine-1,4-diones were successfully synthesized a nd proved to be effective cytotoxic agents against the growth of suspended murine and human leukemias and lymphomas. Selected compounds were also acti ve in human HeLa uterine carcinoma, suspended effusion breast MCF-7 and gli oma HS683 screens. These agents suppressed P388 lymphocytic leukemia DNA sy nthesis after 60 min at 100 muM. Their target appeared to be the de nova sy nthesis pathway with significant inhibition of the activities of both regul atory enzymes of the pathway, i.e. PRPP-amide transferase and IMP dehydroge nase resulting in a reduction in the d[NTP] pool levels for DNA incorporati on. The compounds did not affect de novo pyrimidine synthesis and its regul atory enzymes. Very minor reduction by the agents was noted for the nucleos ide kinases and the DNA and RNA polymerase activities within 60 min. DNA wa s not a target of the agents in that there was no alkylation of the nucleot ide bases, intercalation between base pairs or cross-linking of the DNA str ands; however, the agents did cause P388 DNA strand scission after 24 h at 100 muM.