Thiamine analogs

Carbohydrate metabolism provides the main energy source in coccidia. Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in carbohydrate metabolism—result in suppression of parasitic infestation of chickens by E tenella and E acervulina. A thiamin analog, amprolium—1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been used as an effective anticoccidial agent in chickens and cattle with relatively low host toxicity. The antiparasitic activity of amprolium is reversible by thiamin and is recognized to involve inhibition of thiamin transport in the parasite. Unfortunately, amprolium has a rather narrow spectrum of antiparasitic activity it has poor activity against toxoplasmosis, a closely related parasitic infection. 

Figure 6.1. Thiamin and thiamin analogs, products of tliiaminolysis, and experimental antimetabolites. Relative molecular masses (M,) thiamin, 266.4 (chloride-hydrochloride, 337.3) thiamin monophosphate, 345.3 thiamin diphosphate, 425.3 thiamin triphosphate, 505.3 thiochrome, 262.3 thiamin thiol, 282.4 (oxidizes to thiamin disulfide, 562.7) oxythiamin, 301.8 and pyrithiamin, 420.2.

A case of thiaminase disease due to a fungus has been reported. The agent was Trichosporon aneurolyti-cum which grew in the patient s mouth. Experimentally, the administration of thiamine analogs, such as pyrithiamine and oxythiamine, may also produce thiamine deficiency. The mechanism by which they act is discussed later (see formulas in Fig. 4-5). 

The CD-spectrum obtained upon binding of tetrahydrothiamine diphosphate does not show any alteration compared to the apotransketolase spectrum. Thus, one might conclude that the aminopyrimidine ring of tetrahydrothiamine diphosphate, as in the model system, does not form a charge transfer complex and does not influence the CD of the enzyme in the 250-300 nm region. This means that only the thiazolium ring is responsible for the differences in the 280 nm band of the CD-spectra of the thiamine analogs. 

When it was found that the pyrimidine and thiazole components of thiamin could often replace thiamin, the opportunity was taken to examine the question of the biological specificity of the molecule, since a large number of related pyrimidines and thiazoleshad been prepared by the workers engaged in the synthesis of thiamin. Detailed studies on the specificity of the pyrimidine and thiazole portions of thiamin and of thiamin analogs have been made for Staph, aureus (169) Phycomyces blakesleeanus (38, 305, 306, 333, 334, 348) for various protozoa (236, 237) and for pea-roots (29, 30, 37). [Comparative summaries are given in 159, 211, 309]. 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

An important biological process is the basis for a general coupling method of aldehydes into symmetncal acyloins, such as BETYROIN. The key catalyst is 5-(2-hydroxyethyl)-4-methyl-l,3-thiazole, an analog of thiamin. Condensation of ketones and aldehydes with excess acetonitrile can be accomplished in a simple way to produce a,p-unsaturated nitriles Cyclohexanone leads to CY-CLOHEXYLIDENEACETONITRILE while benzaldehyde gives CINNA-MONITRILE. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Xi, J., Ge, Y., Kinsland, C., McLaeeerty, F. W., and Begley, T. P. Biosynthesis of the thiazole moiety of thiamin in Escherichia coli identification of an acyldisulfide-linked protein-protein conjugate that is fimctionally analogous to the ubiquitin/El complex, Proc Natl Acad Sci USA 2001, 98, 8513-8518. 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

Acid dye method for the analysis of thiamin, 18A, 73 electrophoretic separation and fluorometric determination of thiamin and its phosphate esters, 18A, 91 catalytic polarography in the study of the reactions of thiamin and thiamin derivatives, 18A, 93 preparation of thiamin derivatives and analogs, 18A, 141 preparation of the mono- and pyrophosphate esters of 2-methyl-4-amino-5-hydroxymethylpyrimidine for thiamin biosynthesis, 18A, 162 formation of the pyrophosphate ester of 2-methyl-4-amino-5-hydroxymethylpyrimidine by enzymes from brewers yeast in thiamin biosynthesis, 18A, 203 resolution, reconstitution, and other methods for the study of binding of thiamin pyrophos-... 

Lipid soluble analogs of thiamine (vitamin Bj) 1126 have a number of therapeutic uses, and examples are acetiamine 1127 (R = Me), bentiamine 1127 (R = Ph), fursultiamine 1128, and octotiamine 1129 which has antiinflammatory activity. 

Some analogs of thiamine are biologically active, but have not attained wide use because thiamine itself is cheaply available. 

Examples of nonasymmetric organocatalysts that were introduced in the 1950s include analogs of thiamine reported by Breslow in 1957 as an alternative to cyanide as a catalyst for the benzoin condensation [8]. Asymmetric versions of these thiazolium catalysts were used in organocatalytic benzoin condensations by Sheehan and Hunneman in 1966 [9]. In another important development, in 1969 the nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP), which is now widely used for difficult esterifications, was reported by Steglich [10]. 

Thiamin 0.23 mg or more per 1000 kcal of food consumed and a minimum total of 0.8 mg/day. Replacement of the methyl group on the pyrimidine ring by ethyl, propyl, or isopropyl gives compounds with some vitamin activity, but replacement by hydrogen cuts activity to 5% of the original. The butyl analog is a competitive inhibitor. 

The third type of carbon-branched unit is 2-oxoisovalerate, from which valine is formed by transamination. The starting units are two molecules of pyruvate which combine in a thiamin diphosphate-dependent a condensation with decarboxylation. The resulting a-acetolactate contains a branched chain but is quite unsuitable for formation of an a amino acid. A rearrangement moves the methyl group to the (3 position (Fig. 24-17), and elimination of water from the diol forms the enol of the desired a-oxo acid (Fig. 17-19). The precursor of isoleucine is formed in an analogous way by condensation, with decarboxylation of one molecule of pyruvate with one of 2-oxobutyrate. 

Dwivedi and Arnold (89) determined the thiazole moiety in thiamine by derivatizing first to form the TMS analog. Samples were chromatographed on 3% OV-17 on Chromosorb G (DMCS treated) at 110°C. Vitamin D2 (calciferol) and its analog Vitamin have been the subject of many applications in GC analyses. The compounds have been derivatized as the TMS analog and chromatographed on OV-17 (90) and SE-30 (91) and on 3% silicone on Celite after treatment with antimony trichloride (92). Several references to vitamine E (oi-tocopherol) are included in the review by Kern et al. (39) on GLC determinations of pharmaceuticals and drugs. The acetate was determined on 3% OV-17 on Chrom W-HP at 280°C. Vecci and Kaiser (93) determined Vitamin C as the TMS derivative on 3% SE-30 or 10% XE-60 on Anachrom ABS. Column... 

Exercise 25-31 Why would the intermediate addition product of thiamine to pyruvic acid be expected to decarboxylate readily Support your answer by analogy see Section 18-4. 

Edwards, T. E., and Ferre-D Amare, A. R. (2006). Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition. Structure 14, 1459—1468. 

A number of investigators (15, 16, 17), working with pyruvate decarboxylase, actually isolated the pyruvate adduct to thiamin pyrophosphate, and demonstrated that the enzyme will then decar-boxylate that adduct to yield C02 and acetaldehyde. In an elegant biomimetic study, Lienhard (18, 19) and his collaborators synthesized an analog of this adduct, and showed that it undergoes decarboxylation upon heating in water. Further, the rate is enhanced 105-fold by carry-... 

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