The cytotoxicity of 1-(1-phenylalkylideneamino)-2,4-azetidinediones and their mode of action in human and murine tumor cells.
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.
Izydore
R A
RA
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599-7360, USA.
Zhang
Y
Y
Zhou
X
X
Warren
A E
AE
Wheaton
J R
JR
Hall
I H
IH
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D011687:Purines / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D001384:Azetidines; D011687:Purines