Specific enzyme inhibitors in vitamin biosynthesis. Part 3. The synthesis and inhibitory properties of some substrates and transition state analogues of riboflavin synthase

Abstract

Syntheses of potential inhibitors of riboflavin synthase are described. The tolerance of the enzyme to bulky substituents was investigated by the synthesis of substrate analogues which included lumazines and pyrido [2,3-d]-pyrimidines prepared by condensation of α-diketones and β-keto-aldehydes respectively with appropriate amino substituted uracils. Potential transition-state analogous, including 7-oxolumazines, 7-oxopyrido[2,3-d]pyrimidines, and 6,7-dioxolumaxines were also prepared by similar condensations using α-keto-acid derivatives, dimethyl acetylenedicarboxylate, and oxalate derivatives. Two possible dual affinity inhibitors were also prepared. The potential inhibitors were tested using riboflavin synthase from yeast or from E. coli, and their effectiveness is discussed in relation to the bulk and electronic character of the substituents.