Synthesis and Biochemical Evaluation of Bis(6,7-dimethyl-8-D-ribityllumazines) as Potential Bisubstrate Analogue Inhibitors of Riboflavin Synthase.
The reaction catalyzed by riboflavin synthase utilizes two identical 6,7-dimethyl-8-D-ribityllumazine substrate molecules. Three bis(6,7-dimethyl-8-D-ribityllumazines) were, therefore, synthesized in which the two lumazine moieties were connected through their N-3 nitrogen atoms by polymethylene linker chains containing three, four, and five carbon atoms. The compounds with three and five carbon linkers were found to be very weak inhibitors of riboflavin synthase, having inhibition constants of 320 and >1000 &mgr;M, respectively. In contrast, the bis(lumazine) with a four-carbon linker was much more potent, with an inhibition constant of 37 &mgr;M. These results have potential implications for understanding the distance between the donor and acceptor sites of riboflavin synthase and the orientations of the two 6,7-dimethyl-8-D-ribityllumazine substrate molecules which occupy these two sites.
Cushman
Mark
M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, and Lehrstuhl für Organische Chemie und Biochemie, Technische Universität München, D-85747 Garching, Germany.
Mavandadi
Farahnaz
F
Yang
Donglai
D
Kugelbrey
Karl
K
Kis
Klaus
K
Bacher
Adelbert
A