Oxopurine analogs

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 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,... 

In view of the earlier demonstration that pyrimidone-2 undergoes one-electron reduction, with formation of a dimer identified as 6,6 -6ij-3,6-dihydropyrimidine-2, which is suceptible to quantitative photodissociation to the parent pyrimidone-2, and bearing in mind that 2-oxopurine may be considered a formal analogue of a 5,6-disubstitut-ed pyrimidone-2, it appeared of interest to examine whether an analogous reaction sequence occurs with 2-oxopurine. 

The dimer reduction product of 2-oxopurine also quantitatively regenerated the parent monomer in an alkali catalyzed reaction at room temperature . It is of interest that similar alkaline lability is exhibited by the tram-anti cyclobutane photodimer of thymine The alkaline lability of the purine dihydrodimer may be interpreted as follows the ionized form of the dimer (in alkaline medium) is formally analogous to adducts of two radicals generated by ionizing radiation by the addition of an electron and a proton to pyrimidines or purines ionized in alkaline medium. It was shown by Rao Hayon that ketone radicals are in the enol form and are strong reducers, i.e. they may undergo rapid oxidation. In the case of the ionized 2-oxopurine hydrodimer, this may lead to transfer of two electrons to some acceptor, with concomitant conversion of the dimer to monomers, as follows ... 

Compounds which can be regarded as analogous to reduction products are 1,6-covalent adducts produced by various weak acids including potassium hydrogen sulfite and purine (165) and the 2-oxopurine (166) (75Jcs(pi)224o). 

The method is especially valuable since it permits preparation of 2- and 8-chloropurines which are not readily obtainable by chlorination of the coresponding oxopurines (B-71MI40901, p. 141). The mildness of the procedure makes it especially useful for analogous syntheses of chloropurine nucleosides. Thus 6-thioxo- or 6-methylthio-purine-9- 8-D-ribofuranosides with chlorine in methanol at -10 °C produced the valuable 6-chloropurine-9- 8-D-ribofuranoside in 82% yield (60JA2654). 

Although thermally induced 0-> N methyl group migrations are well documented for the methoxy analogs of xanthine and uric acid, the inter-molecular isomerization of 6-methoxy-7,9-dimethylpurinium chloride (53) to 1,7,9-trimethylhypoxanthinium chloride, in methanol, appears to be the first reported example of a Hilbert-Johnson type reaction involving mono-oxopurines [Eq. (7)]. ° ... 

Keough, D. T., Skinner-Adams, T., Jones, M. K., Ng, A. L., Brereton, I. M., Guddat, L. W., and de Jersey, J. (2006). Lead compounds for antimalarial chemotherapy purine base analogs discriminate between human and P. falciparum 6-oxopurine phosphoribosyltransferases. J. Med. Chem. 49, 7479-7486. 

---