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 pote nt cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synth esis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido t ransferase and LMP dehydrogenase. Other enzymatic activities which were sup pressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleo side reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside ki nase 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 alkylati on 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 mu M.