Design, Synthesis, and Evaluation of Acyclic C-Nucleoside and N-Methylated Derivatives of the Ribitylaminopyrimidine Substrate of Lumazine Synthase as Potential Enzyme Inhibitors and Mechanistic Probes

Abstract

Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin, a vitamin that is involved in many critical biochemical reactions that are essential for the maintenance of life. To obtain inhibitors and structural probes that could be useful in studying the structures of bound reaction intermediates, the ribitylamino N-H moiety of the lumazine synthase substrate was replaced by CH(2) and N-CH(3) groups. The CH(2) replacement unexpectedly and completely abolished the affinity for lumazine synthase, thus revealing a critical, yet unexplained, role of the ribitylamino N-H moiety in conferring affinity for the enzyme. In contrast, the N-CH(3) replacement resulted in an inhibitor of both lumazine synthase and riboflavin synthase. Replacement of the ribitylamino N-H moiety with epimeric C-F moieties led to inhibition of lumazine synthase and riboflavin synthase when combined with the replacement of the 5-amino group with a nitro substituent.

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

“…41,42,48,51,52 The crystal structure of 75 bound to M. tuberculosis lumazine synthase (PDB code: 2C97) 41 encouraged the synthesis of compound 78 , which is described in Scheme 10.…”

“…The S -nucleosides were generally more potent than the corresponding O -nucleosides, as exemplified by the relative activities of the S -nucleosides 49 ( K i 128 μM) and 51 ( K i 198 μM) vs. the O -nucleosides 43 ( K i >1000 μM) and 46 ( K i >1000 μM) against M. tuberculosis lumazine synthase. The S -nucleoside 23 49 having an amino group at C-5 of the pyrimidinedione was found to be a relatively potent inhibitor of the lumazine synthases of S. pombe ( K i 0.16 μ M), B. subtilis ( K i 2.6 μ M), and M. tuberculosis ( K i 31 μ M) and of the riboflavin synthases of M. tuberculosis ( K i 2.5 μ M) and E. coli ( K i 47 μ M), whereas the C- nucleoside analogue 74 51 of the substrate 1 was shown previously to be completely inactive against B. subtilis lumazine synthase. 51 …”

Synthesis and structural studies of C-5 aryl- and C-6 alkyl-substituted pyrimidine derivatives

“…Survey of Cambridge Structural Database ( [19]; errorfree and disorder-free structures of organic compounds with R \ 0.075) has revealed five closely related structures in which two methoxy groups are bonded to the C2 and C4 atoms of the pyrimidine ring [20][21][22][23][24]. Molecular geometry of 3, 4 and 6 agrees with these structures, with the exception of C5-C6 bond in two independent molecules of 4-amino-2,6-dimethoxy-5-nitropyrimidine [20].…”

“…Both methoxy groups in 3, 4 and 6 adopt a synperiplanar conformation with respect to the N1 and N3 atoms of the pyrimidine ring (Table 2). On the contrary, methoxy group attached to the C2 ring atom with respect to the N1 atom in five similar structures [20][21][22][23][24] adopts an antiperiplanar conformation. The hydrogen atom of the dibromomethyl group in 4 ( Fig.…”

New C-aryl alditols from Diels-Alder adducts of sugar nitroalkenes

“…[1][2][3][4][5][6][7][8] Thus, the nitrobenzene derivative chloramphenicol 1,2 inhibits protein synthesis, the methoxybenzene derivative karacilin 3 possesses antiviral activity in vitro against herpes viruses. This type of substances, namely C-aryl alditols, can be considered as acyclo-C-nucleoside analogues that by intramolecular dehydration could provide C-nucleosides; some of the latter, either natural or synthetic, have been reported to have a broad range of useful antitumor, antifungal and antibiotic properties, thus encouraging the development of methodologies toward this class of products.…”