Cytotoxicity of imides-N-alkyl semicarbazones, thiosemicarbazones, acetylhydrazones and related derivatives.
The semicarbazones, thiosemicarbazones and acetyl-hydrazones of phthalimide, o-benzosulfimide, naphthalimide and diphenimide demonstrated potent cytotoxicity against murine and human leukemia cell growth and cultured cell growth from human solid tumors. The major site of inhibition in L1210 leukemia cells was DNA synthesis after 60 min incubated with the agents at 25, 50 and 100 microM. De novo synthesis of purines at the regulatory enzyme sites of PRPP amidotransferase and IMP dehydrogenase were the major targets of the agent. Thymidylate synthetase, dihydrofolate reductase and ribonucleoside reductase activities were inhibited by the agents in a manner which would contribute to the overall reduction of DNA synthesis and cell death. d(NTP) pools were significantly reduced and the evidence suggests that the agents interacted with DNA affording DNA strand scission which would interfere with both template utilization by the polymerases and also ultimately reduce nucleic acid synthesis.
Hall
I H
IH
Division of Medicinal Chemistry & Natural Products, University of North Carolina at Chapel Hill 27599, USA.
Wong
O T
OT
Chapman
J M
JM
D000582:Amidophosphoribosyltransferase / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015195:Drug Design; D005493:Folic Acid Antagonists; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007094:Imides / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D012664:Semicarbazones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005493:Folic Acid Antagonists; D006835:Hydrazones; D007094:Imides; D009363:Neoplasm Proteins; D012664:Semicarbazones; D013882:Thiosemicarbazones; D007168:IMP Dehydrogenase; D013940:Thymidylate Synthase; D000582:Amidophosphoribosyltransferase