The cytotoxicity of copper(II) complexes of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones.
A series of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones copper(II) complexes was evaluated for their cytotoxic mode of action in a variety of human and rodent tumor cell cultures. It was determined that these compounds may induce cytotoxicity by affecting several metabolic pathways including a reduction in de novo purine synthesis, and inhibition of IMP dehydrogenase, and DNA polymerase alpha activities. Selected compounds also demonstrated the ability to inhibit L1210 DNA topoisomerase II activity at micromolar concentrations. These agents were able to antagonize etoposide-induced formation of cleavable complexes as measured by K+/SDS precipitation and in vitro cleavage reactions.
Miller
M C
MC
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360, USA.
Stineman
C N
CN
Vance
J R
JR
West
D X
DX
Hall
I H
IH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects*; D003300:Copper / Q000633:toxicity*; D004256:DNA Polymerase I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007939:Leukemia L1210; D051379:Mice; D009942:Organometallic Compounds / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000633:toxicity*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D003300:Copper; D007168:IMP Dehydrogenase; D004256:DNA Polymerase I