The novel anticancer drug candidate brequinar sodium [DuP 785, NSC 368390, 
6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid 
sodium salt] inhibits dihydroorotate dehydrogenase, the fourth enzyme in the de 
novo pyrimidine biosynthetic pathway leading to the formation of UMP. Sixty-nine 
quinoline 4-carboxylic acid analogs were analyzed as inhibitors of L1210 
dihydroorotate dehydrogenase. This structure-activity relationship study 
identified three critical regions of brequinar sodium and its analogs, where 
specific substitutions are required for the inhibition of the activity of 
dihydroorotate dehydrogenase. The three principal regions are: (i) the C(2) 
position where bulky hydrophobic substituents are necessary, (ii) the C(4) 
position which has a strict requirement for the carboxylic acid and its 
corresponding salts, and (iii) the benzo portion of the quinoline ring with 
appropriate substitutions. These results will be useful in the elucidation of 
the precise nature of the interaction between brequinar sodium and 
dihydroorotate dehydrogenase.