Xanthines tautomerism

Allomaltol, methyl — see Pyran-4-one, 5-methoxy-2-methyl-Allopurinol applications, 5, 343 metabolism, 1, 237 synthesis, 5, 316, 340 tautomerism, 5, 308 xanthine oxidase inhibition by, 1, 173 Allopurinol, oxy-applications, 5, 343 synthesis, 5, 316 Alloxan... 

Tire tautomerism and ionization of xanthosine (21), a 9-substituted xanthine, have been studied by IR spectroscopy in aqueous solution [83MI(2)231].Tlie diketo structure 21 was shown to exist below pH 5, and the 2-enolate anion 22 at neutral and slightly basic pH. 

Most in vitro studies of xanthines have centered around the enzyme xanthine oxidase. Bergmann and co-workers 40-4)) have examined the main oxidative pathways in the xanthine oxidase catalyzed oxidation of purines. The mechanism proposed by these workers 41 > is that the enzyme binds a specific tautomeric form of the substrate, regardless of whether or not that form represents the major structure present in solution. It is then proposed that the purine, e.g., xanthine, undergoes hydration at the N7=C8 double bond either prior to or simultaneously with dehydrogenation of the same position. Accordingly, the process would involve either pathway a or b. Fig. 15. Route a would give a lactim form of the oxidized purine, while b would give the cor-... 

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. 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

Among the poly hydroxypurines the attention of the theoreticians, at least insofar as refined methods of calculation are concerned, has been centered essentially on xanthine and, in particular, on the problem of the N(7)H-N(9)H tautomerism in this compound... 

Concerning the other properties considered in Table XIV the ionization potential of xanthine has been found98 equal to 9.30 eV, a value intermediate, as usual, between those predicted by the PPP and the CNDO methods. The potential predicted for the two tautomeric forms being practically the same, the experimental value does not enable to fix their identity. 

In summary, a 6-substituted pterin was first identified as a structural component of the molybdenum cofactor from sulfite oxidase, xanthine oxidase and nitrate reductase in 1980 (24). Subsequent studies provided good evidence that these enzymes possessed the same unstable molyb-dopterin (1), and it seemed likely that 1 was a constituent of all of the enzymes of Table I. It now appears that there is a family of closely related 6-substituted pterins that may differ in the oxidation state of the pterin ring, the stereochemistry of the dihydropterin ring, the tautomeric form of the side chain, and the presence and nature of a dinucleotide in the side chain. In some ways the variations that are being discovered for the pterin units of molybdenum enzymes are beginning to parallel the known complexity of naturally occurring porphyrins, which may have several possible side chains, various isomers of such side chains, and a partially reduced porphyrin skeleton (46). 

Purines show typical absorption spectra which are useful for the identification and the determination of their structure tautomeric equilibria can also be studied. By comparison of the spectra of natural and synthetic derivatives of purines, the N9 glycosylic linkage was established for nucleosides. The relatively simple spectra of purines show two main bands. Purine shows maxima around 220 nm and at 263 nm in neutral solution. Since the imidazole ring has no characteristic UV absorption, the spectra of purines and pyrimidines show similarities. Similar observations have been made for 7-deazapurines, 8-azapurines etc. In the series of adenine hypoxanthine, and xanthine (at pH 6) only one maximum is observed guanine, isoguanine, and purinc-2,6-diamine show two maxima. 

It was the merit of the theory to have attracted attention to the large variations (2 to 5 Debye units) of dipole moments possibly associated with such tautomerism and to the specific directions of the variation following the nature of the purine. Thus the prediction was that, while the dipole moment of the N(7)H tautomer of purine should be greater than that of its N(9)H tautomer, the dipole moment of the N(7)H tautomer of xanthine should be smaller than... 

Hypoxanthine is oxidized at carbon 2 by both molybdenum hydroxylases, although xanthine oxidase is much more effective as a catalyst in this reaction [ 10]. A methyl substituent in this position prevents oxidation by either enzyme. Introduction of A-methyl substituents into the hypoxanthine nucleus produces dramatic effects on enzymic oxidation rates and also gives some insight into the productive modes of binding to each enzyme. Thus, it has been proposed that hypoxanthine tautomerizes in the xanthine oxidase-substrate complex to the 3-NH-form with a simultaneous shift of the NH-group in the imidazole ring from position 9 to 7 [ 198,200]. In support of this hypothesis, when tautomerism in the imidazole ring is prevented by substitution at N-7 or N-9, such compounds are almost refractory to oxidation (see Table 3.9)... 

Method D is illustrated in Scheme 28 The sodium salt of 8-mercapto-xanthine reacted with chloroacetone and the resulting tautomeric intermediates were dehydrated with ethanolic hydrogen chloride to a tricyclic 6-methyl-thiazolo[2,3-/]-purine-2,4(1/7,3//)-dione 104. 

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