Design, synthesis, and evaluation of 9-D-ribityl-1,3,7-trihydro-2,6,8-purinetrione, a potent inhibitor of riboflavin synthase and lumazine synthase.
Reduction of 5-nitro-6-D-ribitylaminouracil (9) afforded 5-amino-6-D-ribitylaminouracil (1), which reacted with ethyl chloroformate to yield 5-ethylcarbamoyl-6-D-ribitylaminouracil (12). The latter compound was cyclized to 9-D-ribityl-1,3,7-trihydropurine-2,6,8-trione (13), which was found to be a relatively potent inhibitor of both Escherichia coli riboflavin synthase (K(i) 0.61 microM) and Bacillus subtilis lumazine synthase (K(i) 46 microM). Molecular modeling of the lumazine synthase-inhibitor complex indicated the possibility for hydrogen bonding between the Lys135 epsilon-amino group of the enzyme and both the 8-keto group and the 4'-hydroxyl group of the ligand. A bisubstrate analogue of the riboflavin synthase-catalyzed reaction, 1,4-bis[1-(9-D-ribityl-1,3,7-trihydropurine-2,6,8-trionyl)]butane (18), was also synthesized using a similar route and was found to be inactive as an inhibitor of both riboflavin synthase and lumazine synthase.
Cushman
M
M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA. cushman@pharmacy.purdue.edu
Yang
D
D
Kis
K
K
Bacher
A
A
D001412:Bacillus subtilis / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004926:Escherichia coli / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis*; D011994:Recombinant Proteins / Q000737:chemistry; D012255:Ribitol / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D012258:Riboflavin Synthase / Q000037:antagonists & inhibitors*
C443719:9-ribityl-1,3,7-trihydro-2,6,8-purinetrione; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011687:Purines; D011994:Recombinant Proteins; D012255:Ribitol; C044822:6,7-dimethyl-8-ribityllumazine synthase; D012258:Riboflavin Synthase