8-Aza guanine

Evans, H.J., and Vijayalaxmi. Induction of 8-aza-guanine resistance and sister chromatid exchange in human lymphocytes exposed to mitomycin C and X rays in vitro. Nature 292 601-605, 1981. 

In one of the few known attempts to prepare a deoxyriboside, 2-deoxy-3,5-di-0-p-tolyl-D-eo t/jr(>-pentofuranosyl chloride and the sUylated 8-aza-guanine gave a mixture of both a and fi anomers, of which the p has the... 

Azahypoxanthine prevented cloning of human malignant HeLa S3 cells, but not of normal human cells, whereas 8-azaadenine prevented cloning of either type. °° 8-Azainosine (1 fiM) inhibited colony formation by human epidermoid (type 2) carcinoma cells in culture. In cell-free extracts of HeLa cells, protein synthesis was inhibited by the incorporation of 8-aza-guanine into the mRNA of polysomes, in which it blocked formation of peptide bonds. ... 

Since specificity of the nucleoside phosphorylases varies, enzymes that catalyze the formation of the nucleosides of the so-called fraudulent purine bases, 6-mercaptopurine (purine-6(lH)-thione) and 8-aza-guanine (5-amino-t -triazolo[ 4,5-d]pyrimidin-7(6if)-one), have been found, and gram quantities of 8-azaguanosine have been isolated. ... 

The directed synthesis of Bis-group compounds by the E. coli-Factor B system has some resemblance to the incorporation of 8-aza-guanine into the nucleic acid of the tobacco mosaic virus, as proved by the isolation of 8-azaguanylic acid from the nucleic acid (Matthews, 1954). Inhibition by 8-azaguanine is attributable to the inability of the virus particles to multiply when they contain 8-azaguanine in their nucleic acid. 

N(8)H, and N(9)H in a large series of 8-azapurines,152-157 made a theoretical study of their properties particularly advantageous. Such a study158 has been carried out for the 8-aza derivatives of purine (66), adenine (67). guanine (68), xanthine (69), and hypo-xanthine (70). The principal results are summed up in Table XVII. 

The 5 -(phenylmethoxy)alaninyl phosphate derivative of 330 was found to be active against HIV-1 and HIV-2 with a potency similar to that of the 8-deaza analog and the 5 -triphosphate derivative of 330 was an active inhibitor of HIV-1 recombinant reverse transcriptase (94JMC3534). The (R) and (5)-8-aza-9-[(2-phosphonomethoxy)propyl]guanines [(/ )- and (5)-8-aza-PMPG] (337) were tested in vitro for anti-HIV activity. The (S)-isomer was found to be less potent than its (/ )-enantiomer (95JMC4007). 

A series of 7-alkynylamino-7-deaza-dG analogues was examined for their ability to stabilise DNA duplexes. As the length of the alkynyl chain increases, duplex stability decreases. The incorporation of 7-deaza-8-aza-dG residues into guanine-rich sequences reduces the formation of guanine quartets due to the inability to form Hoogsteen base pairs. The N -glycosylated 7-deaza-8-aza-dG derivative (90) forms stable base pairs with iso-dC in antiparallel duplexes and with dC in parallel duplexes, but does not form guanine quartet... 

Conventional methods have been used to prepare ribonucleoside analogues from 2-(l//)pyrazinone, 3,5-disubstituted pyridines (including a-anomers), 6-methyl-l,3-oxazine-2,4-dione and 6-methyluracil, 2-alkyl-4,5-dicarboxamido-imidazoles, 7-membered ring analogues (4) and (5) of uracil and tetrahydro-uracil [one diastereomer of (4) being the most potent inhibitor of cytidine deaminase yet discovered], 2-alkylthioadenine, 8-aza-3-deaza-guanine/ ... 

Fig. 5 Structures of various modifications studied for optimal TLR9-mediated immune response. Cytosine modifications C 2 -dC, Cj 5-hydroxy-2 -dC, C2 5-propyne-2 -dC, C3 furano-2 -dT, C4 pyrrolo-2 -dC, C5 dF, Cg 4-thio-2 -dU, Cy N -methyl-2 -dC, Cs N -ethyl-2 -dC, C9 P-iso-2 -dC, and Cio arabinoC. Guanine modifications G 2 -dG, Gj 7-deaza-2 -dG, Gy 7-deaza-8-aza-2 -dG, G3 9-deaza-2 -dG, G4 6-(9-methyl-2 -dG, G5 N -methyl-2 -dG, Gg N -methyl-2 -dG, Gy 6-thio-2 -dG, Gs 2 -deoxyinosine, G9 8-G-methyl-2 -dG, Gw 8-G-allyl-2 -dG, and Gn arabinoG. Linkers (L) Lj glycerol (1,2,3-propanetriol), Ly (5)-(-)-l,2,4-butanetriol, L3 1,3,5-pentanetriol, L4 cis, cis-l,3,5-cyclohexanetriol, L cis,trans-l,3,5-cyclohexanetriol, Lg l,3,5-tris(2-hydroxyethyl) isocyanurate, Ly tetraethyleneglycol, and Lg hexaethyleneglycol...

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