Pteridine formation

Unsymmetrical 1,2-dicarbonyl compounds lead to mixtures of structural isomers. a-Keto aldehydes undergo regioselective pteridine formation the corresponding a,a-dichloro ketones behave complementarily, as documented by the reaction of triaminouracil (3) with phenylglyoxal and a,a-dichloroacetophenone, respectively ... 

Pteridine formation occurs chemoselectively the primary condensation step is likely to proceed via the nitroso group giving rise to the imine 5, which cyclizes via the remaining NH2 group with the terminal function of the side chain (C=0, ester, nitrile, etc.). 

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

As a result of the 7r-deficiency of the pteridine nucleus, alkyl pteridines are activated in the a-positions. The common reactions based on C—H acidity are found with a wide variety of compounds. Bromination of 6- and 7-methyl groups leads to mono- and di-substitution selective formation of the monobromomethyl derivatives has not yet been achieved satisfactorily. 6-Methylisoxanthopterin is claimed to give the 6-bromomethyl derivative with bromine in acetic and sulfuric acids at 100 °C for 2 min (50ZN(B)132) and with 1,7-dimethyl-lumazine a 90% yield of the 7-bromomethyl derivative (60CB2668) is obtained after 4h... 

Oxidations in the pteridine series comprise (i) replacement of hydrogen by hydroxyl, (ii) glycol formation at the central C=C bond (iii) the removal of hydrogen atoms from dihydro and tetrahydro derivatives. 

Pteridine-2-sulfonic acid, 4-oxo-3,4-dihydro-synthesis, 3, 300 Pteridine-2,4,6,7-tetrone formation, 3, 308 reactions, 3, 296 synthesis, 3, 291... 

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

In many cases, addition or removal of water proceeds sufficiently slowly that some of the physical properties of unstable species (such as hydrated neutral quinazoline or anhydrous 2-hydroxypteridine) can be observed. In these cases, reaction kinetics can also be examined. Addition of water to pteridine is of special interest in relation to studies of the formation and hydrolysis of Schiflf bases. The reaction proceeds in two reversible stages, 3 4 5 ... 

In studies of the hydration and dehydration of pteridine and the methylpteridines, but not levelled out as solutions were made more acid. This was explained by assuming that hydronium ion catalysis of the reactions proceeded only by the formation of the cations of HY+ and HX+, respectively. This effect is strikingly shown by 1,3,8-triazanaphthalene, for which the pH-rate profile of is V-shaped between pH 6.82 and 10.29 but levels out and remains constant from pH 5.3 down to, at least, 2.4. ... 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Among its inhibitors are methotrexate (MTX), trimethoprim, and other derivatives of pyrimidines, triazines, pteridines, and related heterocyclic compounds. Some of these inhibitors, such as MTX, bind more tightly to Escherichia coli enzyme than does the substrate dihydrofolate. This fact has been attributed to ion-pair formation between protonated MTX and a negative carboxyl, presumably Asp-27, as well as to hydrophobic interactions.33... 

Rearangement of furoxans leads to the formation of new heterocyclic systems derivatives of triazoles, diazoles, isoxazoles, and pyrimidinones. For example, on the basis of the experimental results using labeled compound 52-15N , the formation of 8-phenyltheophylline 53, the 1,3-dimethylalloxazines (54 n = 0, 1), and l,3,7,9-tetramethyl-l//,9//-pyrimido[5,4-g]-pteridine-2,4,6,8-tetraone 55 in the thermal reaction of the iV-oxide 52 with benzylamine, aniline, or piperidine and the generation of NO or NO-related species in the reaction with iV-acetylcysteamine were reasonably explained by... 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

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