Riboflavin analogues

Later, a completely different and more convenient synthesis of riboflavin and analogues was developed (34). It consists of the nitrosative cyclization of 6-(A/-D-ribityl-3,4-xyhdino)uracil (18), obtained from the condensation of A/-D-ribityl-3,4-xyhdine (11) and 6-chlorouracil (19), with excess sodium nitrite in acetic acid, or the cyclization of (18) with potassium nitrate in acetic in the presence of sulfuric acid, to give riboflavin-5-oxide (20) in high yield. Reduction with sodium dithionite gives (1). In another synthesis, 5-nitro-6-(A/-D-ribityl-3,4-xyhdino) uracil (21), prepared in situ from the condensation of 6-chloro-5-nitrouracil (22) with A/-D-ribityl-3,4-xyhdine (11), was hydrogenated over palladium on charcoal in acetic acid. The filtrate included 5-amino-6-(A/-D-ribityl-3,4-xyhdino)uracil (23) and was maintained at room temperature to precipitate (1) by autoxidation (35). These two pathways are suitable for the preparation of riboflavin analogues possessing several substituents (Fig. 4). 

Research on riboflavin kinase and FAD synthetase has a long history that has been addressed in an earlier review. Notably, the substrate spedfities of enzymes from various sources have been studied in some detail using collections of riboflavin analogues. This chapter focuses on recent developments. In light of the general importance of these enzymes in all organisms, the number of recent studies appears low. 

A number of FAD analogues containing modifications in the isoalloxazine moiety have been prepared by incubation of the riboflavin analogues with the flavokinase/FAD synthetase system of Brevibacterium ammoniagenes. All... 

Sarett, H. P. The effect of riboflavin analogues upon the utilization of... 

Reaction of 2-amino-2-deoxypentoses with pentane-2,4-dione and 1-phenyl-butane-1,3-dione afforded substituted pyrroles (e.g., 41) and the riboflavin analogue (42) was prepared by condensation of l>-ribose with 5-amino-o-cresol, followed by cyclocondensation of the product with violuric acid. Reaction of dehydroascorbic acid with o-phenylenediamine followed by aroylhydrazides afforded compounds of the type (43), the side-chains of which have been further elaborated. The acid derived by oxidation of 2,3 4,5-di-0-iso-... 

Figure 36.1 Mutual transformations of riboflavin analogues naturally occurring in the body. The flgure presents mutual conversions of riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) which occur during the absorption of the vitamin in the mammalian intestinal tract.

The inhibitory effect of uptake was observed during the analysis of the absorption of riboflavin analogues lumiflavin (riboside side chain is exchanged for a methyl group), lumichrome (devoid of a riboside side chain), 8-[NH2]-riboflavin and iso-riboflavin. Simultaneously, an insignificant effect was noted for D-ribose, panthotenic acid (substances with a pterin ring), suggesting that... 

The isomeric riboflavin phosphates can also be separated by ion pair chromatography on reversed-phase HPLC columns (7). However, the reversed-phase technique was found to be more reproducible. Milligram amounts of pure 5 -FMN (>95%) can be obtained by preparative HPLC, which may be significant in work with rare riboflavin analogues and with isotope-labeled samples (7,27). 

The riboflavin analogue 20 has been made in order to study its binding to riboflavin synthetase. ... 

The microbial assay is based on the growth of l ctobacillus casei in the natural (72) or modified form. The lactic acid formed is titrated or, preferably, the turbidity measured photometrically. In a more sensitive assay, l euconostoc mesenteroides is employed as the assay organism (73). It is 50 times more sensitive than T. casei for assaying riboflavin and its analogues (0.1 ng/mL vs 20 ng/mL for T. casei). A very useful method for measuring total riboflavin in body fluids and tissues is based on the riboflavin requirement of the proto2oan cHate Tetrahjmenapyriformis which is sensitive and specific for riboflavin. 

The tautomerism of some deaza analogues of riboflavin has been studied (77TL2551). The tautomerism of 3-ethoxalylmethyl- and 3-acetonyl-pyrido[2,3-f ]pyrazin-2-ones is fully discussed in (71TH21500 p. 68)... 

Catalysis by flavoenzymes has been reviewed and various analogues of FAD have been prepared e.g. P -adenosine-P -riboflavin triphosphate and flavin-nicotinamide dinucleotide ) which show little enzymic activity. The kinetic constants of the interaction between nicotinamide-4-methyl-5-acetylimidazole dinucleotide (39) and lactic dehydrogenase suggest the presence of an anionic group near the adenine residue at the coenzyme binding site of the enzyme. ... 

Antagonists of riboflavin include isoriboflavin, lumiflavin, aiaboflavin, hydroxyethyl analogue, formyl methyl analogue, galactoflavin, and flavin-monosulfate. Synergists include vitamins A. B, B(l, and B12, niacin, pantothenic acid, folic acid, biotin, tetraiodothyronine (thyroxine), insulin, and somatotrophin (growth hormone). 

Fouty B, Frerman F, Reves R. Riboflavin to treat nucleoside analogue-induced lactic acidosis. Lancet 1998 352 291-2. 

Manesiotis, P. Hall, A. J. Courtois, J. Irgum, K. Sellergren, B., An artificial riboflavin receptor prepared by a template analogue imprinting strategy, Angewandte Chemie, Intern. Ed. 2005,44,3902-3906... 

Luzzati R, DelBravo P, DiPerri G, Luzzani A, Concia E. Riboflavine and severe lactic acidosis. Lancet 1999 353 901-902. Claessens YE, Cariou A, Chiche JD, Dauriat G, Dhainaut JF. L-carnitine as a treatment of life-threatening lactic acidosis induced by nucleoside analogues. AIDS 2000 14 472-473. 

The hypothesis, based on the kinetic findings, that Compounds Q and Q( are diastereomers was confirmed by circular dichroism (CD) spectroscopy (Figure 18) and X-ray structure analysis of pentameric riboflavin synthase from Ai. jannaschii in complex with the substrate analogue, 8-ribityl-6,7-dioxo-8-ribityllumazine (38). 

The synthesis and characterization of inhibitors for lumazine synthase and riboflavin synthase have been pursued by several research groups over extended periods, and compounds with high in vitro activity have been reported/ °" Unfortunately, none of the known compounds had significant in vivo activity. Most probably, the synthetic compounds, being structural analogues of substrates, products, or intermediates, had insufficient drug-like properties. They may have typically failed to penetrate into the bacterial cells. 

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