29161-67-9Relevant academic research and scientific papers
Design, synthesis, and evaluation of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase
Cushman, Mark,Yang, Donglai,Gerhardt, Stefan,Huber, Robert,Fischer, Markus,Kis, Klaus,Bacher, Adelbert
, p. 5807 - 5816 (2007/10/03)
A series of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-D-ribityllumazine were synthesized as inhibitors of both Escherichia coli riboflavin synthase and Bacillus subtilis lumazine synthase. The compounds were designed to bind to both the ribitylpurine binding site and the phosphate binding site of lumazine synthase. In the carboxyalkyl series, maximum activity against both enzymes was observed with the 3′-carboxypropyl compound 22. Lengthening or shortening the chain linking the carboxyl group to the lumazine by one carbon resulted in decreased activity. In the phosphonoxyalkyl series, the 3′-phosphonoxypropyl compound 33 was more potent than the 4′-phosphonoxybutyl derivative 39 against lumazine synthase, but it was less potent against riboflavin synthase. Molecular modeling suggested that the terminal carboxyl group of 6-(3′-carboxypropyl)-7-oxo-8-D-ribityllumazine (22) may bind to the side chains of Arg127 and Lys135 of the enzyme. A hypothetical molecular model was also constructed for the binding of 6-(2′-carboxyethyl)-7-oxolumazine (15) in the active site of E. coli riboflavin synthase, which demonstrated that the active site could readily accommodate two molecules of the inhibitor.
Specific enzyme inhibitors in vitamin biosynthesis. Part 3. The synthesis and inhibitory properties of some substrates and transition state analogues of riboflavin synthase
Al-Hassan, Saieba S.,Kulick, Russell J.,Livingstone, Daniel B.,Suckling, Colin J.,Wood, Hamish C. S.,Wrigglesworth, Roger,Ferone, Robert
, p. 2645 - 2656 (2007/10/02)
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 analogues, including 7-oxolumazines, 7-oxopyrido[2,3-d] pyrimidines, and 6,7-dioxolumazines 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.
