Pteridines, function

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). 

No simple pteridine 1- or 3-oxides are yet known. If the AT-atom of an amide function is formally oxidized, tautomerism favours the cyclic hydroxamic acid structure, as found for 3-hydroxypteridin-4-one (55JA3927), 1-hydroxylumazine (64JOC408) and 2,4-diamino-8-hydroxypteridin-7-ones (75JOC2332). 

The reactivity of the amino groups at the pteridine nucleus depends very much upon their position. All amino groups form part of amidine or guanidine systems and therefore do not behave like benzenoid amino functions which can usually be diazotized. The 4-, 6-and 7-amino groups are in general subject to hydrolysis by acid and alkali, whereas the 2-amino group is more stable under these conditions but is often more susceptible to removal by nitrous acid. 

When hydroxypteridines are considered, it must be borne in mind that these compounds exist principally in the pteridinone forms, containing thermodynamically stable amide functions, and consequently have low reactivity. Their stability towards acid and alkali correlates well with the number of electron-donating groups which apparently redress the deficit of ir-electrons located at the ring nitrogen atoms. Quantitative correlations can be seen in the decomposition studies of various pteridinones (Table 7). These results are consistent with the number of the oxy functions and their site at the pteridine nucleus. The... 

The 5,6-amide function has been found to be unusually reactive in the 2,4-disubstituted pteridin-6-one series, forming the corresponding 6-alkoxy derivatives, e.g. (141), with alcoholic HCl directly (62CB755, 70CB735). 

Among the substitution reactions involving the ring nitrogen atoms of the pteridine nucleus, alkylations of amide functions are preeminent. Under base-catalyzed conditions it is usually the nitrogen atom adjacent to the carbonyl function which is substituted... 

There are a series of non-mobile coenzymes based on the so-called isoalloxine rings, which include flavins and pteridines. Their early function was the transfer of hydrogen inside membranes or in complicated enzymes, so we have... 

The function of pteridines in the metabolism of some microorganisms was studied. They were found to influence the production of vitamin Bi2... 

Reductive sequences involving flavoproteins may be represented as the reverse reaction, where hydride is transferred from the coenzyme, and a proton is obtained from the medium. The reaction mechanism shown here is in many ways similar to that in NAD+ oxidations, i.e. a combination of hydride and a proton (see Box 11.2) it is less easy to explain adequately why it occurs, and we do not consider any detailed explanation advantageous to our studies. We should register only that the reaction involves the N=C-C=N function that spans both rings of the pteridine system. 

The synthesis of deoxysepiapterin (82) has been recently achieved by homo-lytic nucleophilic substitution of the pteridine nucleus by acyl radicals (505). Since this substitution arises preferentially at the most electron-deficient 7 position, protection at 7 position is necessary for nucleophilic attack at the 6 position. 2,4-Diamino-7-methylthiopteridine (597) and 2-amino-4- -pentyloxy-7-n-pro-pylthiopteridine (600), protected by the thio function, can be used as starting materials. Homolytic acylation of 597 with the system propionalde-hyde/Fe2+//ert-butylhydroperoxide afforded 6-propionylpteridine (598) in good yields, which could be transformed to deoxysepiapterin (82) by selective hydrolysis followed by deprotection of the thio function (Scheme 75). Deoxysepiapterin (82) can also be prepared by a similar procedure from 600. 

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. 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

Nobuhiro Sato was born in Niigata, Japan, in 1945. He received his B.Sc. degree from Yokohama City University in 1968 and his Ph.D. degree from Tokyo Metropolitan University in 1981. After a postdoctoral position with E. C. Taylor at Princeton University, he returned to japan, where he is now professor of chemistry at Yokohama City University. His research interests include synthesis and reactivity of heterocyclic compounds, particularly pyrazines and pteridines, as optically functional materials or bioactive products. 

Tautomerism is common in pteridine derivatives and the favored tautomers should be represented by the structural formulas. Amino groups exist as such and not in the iminodihydro form whereas the hydroxy and thiol functions 9 located adjacent or para to a ring nitrogen atom prefer the thermodynamically more stable amide (lactam) and thioamide (thioxo) configuration 8 (Scheme 1) . 

The introduction of substituents into position 7 of a 2,4-disubstituted pteridine can be effected very cleanly by the use of acyl radicals typically and has been known for many years. Treatment of aldehydes with /-butyl hydroperoxide and iron(ll) generates acyl radicals which add selectively to the 7-position. A recent exploitation of this chemistry has provided a large number of new examples including both aryl and alkyl acyl radicals as reagents <2004PTR129> pA , data have been compiled (Section 10.18.4) and many nucleophilic substitution reactions of the 7-acylated pteridines and functional group modifications have been described (Section 10.18.7.2). 

In some cases, side reactions were observed. When 4-chlorophenyl isocyanate reacted with iminophosphorane 135 (R= Pr ), along with the corresponding pteridin-4(377)-one (43%), the hydrolyzed compound, 3-isopropylpteridine-2,4-(177,377)-dione (26%), was also isolated. In cases with additional functional groups in the pteridine substrate such as esters, polycyclic compounds such as the imidazo[2,T ]pteridine derivative 138 (37%) were obtained. Similarly, Wallyl and W(l-methylprop-2-enyl) groups in 137 gave imidazo[2,l- ]pteridines 139 by iodoamination. 

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