Oxopurines

Other classes of low-molecular-weight TLR7-selective compounds such as loxoribine, 20 [67], a prodrug of isatoribine, ANA-975, 21 [68], oxopurine analogs such as 22 [69], and stabilized immunomodulatory RNAs are in development [70]. 

The predominant binding site in 9-substituted 6-oxopurines (guanine and hypoxanthine derivatives) is the N7 atom of the base (Figure 6). The prevailing keto tautomer requires proton at N1 even in mildly acidic conditions, which efficiently prevents platination of the N1 site [7]. Under neutral and basic conditions competition of Pt(II) between the N1 and N7 sites has been reported. Attachment of Pt(II) to the N7 atom acidifies the N1H proton and facilitates coordination of additional platinum ions to both N1 and N3 [7]. In N7,N9-blocked 6-oxopurines, the N1 site is the major coordination site [7,24],... 

With aquated Pt(II) compounds, numerous studies have revealed the kinetic preference of the 6-oxopurine N7 site [15,35]. In addition to the favorable electrostatic potential mentioned above [23] also steric factors seem to favor coordination to the guanine N7 site, in particular [36]. Estimated relative steric parameters (in parenthesis) suggest that the guanine N7 (1.00) and hypoxanthine N7 (1.03) atoms are the least sterically hindered binding sites in alkylated nucleobases, followed by the adenine N7 (1.17) and deprotonated hypoxanthine N1 (1.17) sites and the deprotonated N3 atoms of the different pyrimidine bases (1.39 for U, 1.44 for T, and 1.56 for C), while the adenine N1 (1.58) and... 

Dimroth rearrangement under acidic conditions has also been reported acid hydrolysis of 1-hydroxyisoguanine provides 6-hydroxylamino-2,3-dihydro-2-oxopurine (Scheme IV.29) (67JOC1151). 

There are three common approaches to the displacement of amine substituents from purines. First, diazotization and dediazoniation have been used to replace amine substituents, primarily with hydrogen or hydroxyl, carboxyl, and halide functionalities. Second, the S Ar reactions of quaternary ammonium substituents have provided useful synthetic adjuncts to the displacement reactions of halopurines. Finally, of increasing importance has been the conversion of aminopurines (or oxopurines) to N-linked 1,2,4-triazoles (and other azoles), which function as pseudohalogens and can be displaced by nucleophiles or take part in transition metal-catalyzed reactions. 

Modification of inosine 5 -monophosphate occurs by two routes oxidation by an NAD requiring enzyme to the 2-oxopurine and hence to guanosine 5 -monophosphate, or aspartate dependent amination at C-6 by a sequence similar to that employed in the conversion of (16) to (18) described above to give adenine 5 -monophosphate. 

In simple purines the imidazole ring is usually involved in anion formation. The strong resemblance shown between the spectrum of the anion (6) of 8-oxopurine and that of 7-methyl-8-oxopurine (7)... 

Purine-6-thione, in forming the 8-oxopurine, behaves like other 6-substituted purines108-108 used with this enzyme system. The exception to the rule is hypoxanthine which suffers attack at the... 

The interrelationship between the 2- and 8-positions is exemplified by 2-oxo-103 and 8-oxopurine, which are both converted by xanthine oxidase to 2,8-dioxopurine. Some unexpected results of oxidation can best be explained by assuming stereospecific factors. Thus, whereas purine, its 2-methyl, and its 2-amino derivatives give the 6-oxo derivatives, the 2-phenyl- and 2-oxopurines mentioned above oxidize at the 8-position.112... 

The sulfur-containing analogs of the oxopurines, because of the greater nucleophilicity of sulfur, will alkylate on either nitrogen or sulfur. Aqueous media dispose toward S-alkylation, whereas aprotic solvents are more likely to lead to nuclear alkylation. For example,... 

Though once commonly proposed, direct M7 )-0(6 )-chelalion by a metal ion in 6-oxopurines is now accepted to occur only in special cases [38] [40] [44], Any chelation is indirect, through a metal-ion-bound water molecule, for example [45]. 

The sizable enhancement by 1.6 log units of (dien)Pd11 binding to N(7) of the 6-oxopurines, inosine and guanosine, compared to adenosine on a ba-... 

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