2,2'-[(3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)diimino]bis-benzoic acid (DBDB, "Redoxal") and 1-(p-bromophenyl)-2-methyl-1H-naphth[2,3,- d]imidazole-4,9-dione (BNID) were selected by the computer algorithm COMPARE as providing excellent correlations, in terms of human tumor cell toxicity, with two dihydroorotate dehydrogenase (DHOD) inhibitors: dichloroallyl lawsone (r>0.8) and brequinar (r>0.74). When Redoxal and BNID (10muM) were incubated with MOLT-4 and L1210 cells for 16-24h, proliferation was reduced by 50-80% and UTP and CTP pools were reduced by over 90% Addition of either uridine or cytidine (50~M) antagonized this cytotoxicity; uridine corrected the (UTP) and (CTP) deficit, whereas cytidine corrected only the (CTP) deficit. Cellular extracts from MOLT-4 cells treated with 5~M Redoxal or BNID and exposed to [14C] sodium bicarbonate showed increased radioactive incorporation into dihydroorotic and N-carbamyl-L-aspartic acids, but no flux into cytidine or uridine mono-, di- and triphosphates. Thus it appears that both Redoxal and BNID were correctly predicted by COMPARE to be inhibitors of de novo pyrimidine biosynthesis.
NIH ExPorter
NIH ExPorter