8-Azapurine riboside

To test whether we could accurately calculate the fold-difference of ADA inhibitory potency between purine riboside (8) and analogues of purine riboside, we selected 8-azapurine riboside (9) for our studies. Compound 9 was reported to be a 400-fold more potent ADA inhibitor relative to 8 despite differing from 8 only by the replacement of C8 with a nitrogen (Figure 8).19 The molecular reason for this enhancement in potency was not determined, but could be due either to enhanced hydration or enhanced ADA binding affinity of the hydrated species or both. To determine the reason,... 

Figure 8. Purine riboside/8-azapurine riboside and corresponding hydrates...

An alternative explanation for the 400-fold improvement in inhibitory potency exhibited by 8-azapurine riboside (9) is that the 8-aza analogue hydrates to a much larger extent than purine riboside (8). Calculation of the relative hydration free energy difference between 9-methylpurine and 8-aza-... 

Glycosides. Because of their possible therapeutic value in acting as antagonists of the natural purine riboades (nucleosides), interest remains high in attempts to improve yields of the 8-azapurin-9-/ -D-ribosides, as weU as analogs with other sugar residues. 

The sieves method is exemplified by the refluxing, in benzene, of 6-meth-ylthio-8-azapurine with 2,3,5-tri-O-acetyl- D-ribofuranosyl 1-chloride and molecular sieves (Linde AW-500) (21 h). This gave a 2 1 ratio of the 9- and 8-triacetylribofuranosides of 6-methylthio-8-azapurine, separated on a silica column. Treatment with ammonia gave a 61% yield of pure 8-azaadenosine (20). The ratio of ribosides could be improved to 6 1 by an increase in time and temperature. 2-Acetamido-6-methylthio-8-azapurine was ribosy-lated similarly. 

Methyl-6-methylthio-8-azapurine, refluxed (1 h) with methanolic sodium methoxide, gave 6-methoxy-8-methyl-8-azapurine in 50% yield. 3-Chloroperbenzoic acid and 8-methyl-2-methylthio-8-azapurine, stirred in chloroform (20 °C, 12 h) yielded 60% of 8-methyl-2-methylsulfinyl-8-aza-purine. The same acid converted 6-amino-2-methylthio-8-azapurine 9-riboside to the 2-methylsulfonyl analog in 80% yield (50°C, 1 h). 6-Amino-... 

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