Cytotoxicity of 2-ethenyl-2,3-dihydrophthalazine-1,4-diones in murine and human tumor cultured cells.
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.
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
I H
IH
Hall
D W
DW
Covington
J R
JR
Wheaton
R A
RA
Izydore
X
X
Zhou
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010793:Phthalazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D010793:Phthalazines