Structure-activity relationship of quinoline carboxylic acids. A new class of inhibitors of dihydroorotate dehydrogenase.
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.
Chen
S F
SF
Cancer Chemotherapy Research Program, E.I. Du Pont de Nemours & Co., Wilmington, DE 19898.
Papp
L M
LM
Ardecky
R J
RJ
Rao
G V
GV
Hesson
D P
DP
Forbes
M
M
Dexter
D L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D007939:Leukemia L1210 / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D013329:Structure-Activity Relationship; D011798:Quinaldines
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D000090722:Dihydroorotate Dehydrogenase; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C046943:brequinar; D011798:Quinaldines