Design and synthesis of tetrahedral intermediate analogues as potential dihydroorotase inhibitors.
Three new heterocyclic analogues (4-6) of dihydroorotic acid were designed, synthesized, and tested as inhibitors of dihydroorotase. Each compound possessed a tetrahedral sulfur atom at the position equivalent to carbon 4 in the dihydroorotate ring in an attempt to mimic the presumed tetrahedral transition state in the course of the enzymatic reaction. Additionally, N-carbamyl-3-phosphonoalanine was prepared and evaluated as a dihydroorotase inhibitor. Compounds 4 and 6 were modest inhibitors (I50's of 0.52 and 0.18 mM, respectively), but the other candidate inhibitors showed little inhibition at 1 mM.
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D004080:Dihydroorotase / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology; D013455:Sulfur
D006571:Heterocyclic Compounds; D013449:Sulfonamides; D013454:Sulfoxides; C004768:4,5-dihydroorotic acid; D009963:Orotic Acid; D013455:Sulfur; D000581:Amidohydrolases; D004080:Dihydroorotase