Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells.
Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.
Burnham
B S
BS
Department of Chemistry, University of North Carolina at Asheville 28804, USA.
Gupton
J T
JT
Krumpe
K
K
Webb
T
T
Shuford
J
J
Bowers
B
B
Warren
A E
AE
Barnes
C
C
Hall
I H
IH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D003374:Coumarins; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004798:Enzymes / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007546:Isoquinolines; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D004798:Enzymes; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D011720:Pyrazoles; D011758:Pyrroles; C116876:lamellarin O; C116875:lukianol A; D012313:RNA; D004247:DNA