O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

摘要

Lumazine synthase catalyzes the penultimate step in thenbiosynthesis of riboflavin, while riboflavin synthase catalyzes the last step. ONucleoside,nS-nucleoside, and N-nucleoside analogues of hypotheticalnlumazine biosynthetic intermediates have been synthesized in order tonobtain structure and mechanism probes of these two enzymes, as well asninhibitors of potential value as antibiotics. Methods were devised for thenselective cleavage of benzyl protecting groups in the presence of other easilynreduced functionality by controlled hydrogenolysis over Lindlar catalyst.nThe deprotection reaction was performed in the presence of other reactivenfunctionality including nitro groups, alkenes, and halogens. The targetncompounds were tested as inhibitors of lumazine synthase and riboflavin synthase obtained from a variety of microorganisms. Inngeneral, the S-nucleosides and N-nucleosides were more potent than the corresponding O-nucleosides as lumazine synthase andnriboflavin synthase inhibitors, while the C-nucleosides were the least potent. A series of molecular dynamics simulations followednby free energy calculations using the Poisson−Boltzmann/surface area (MM-PBSA) method were carried out in order tonrationalize the results of ligand binding to lumazine synthase, and the results provide insight into the dynamics of ligand bindingnas well as the molecular forces stabilizing the intermediates in the enzyme-catalyzed reaction.