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CLASSIFICATION OF PURINE NUCLEOSIDE ANALOGS BASED ON MULTIPLE BIOLOGICAL AND BIOCHEMICAL PARAMETERS: 145

On the basis of a systematic study of the effects of growth inhibitory purine and purine nucleoside analogs on 29 biological and biochemical parameters, we have classified them into 12 major groups. Drugs whose toxicity is reversed by adenine and hypoxanthine are divided into 3 groups. In addition to reduction of formate incorporation, altered ribonucleotide pool sizes and inhibition of macromolecule synthesis, 1 group is metabolized to drug nucleotides whereas the 2nd group is not. The 3rd group has diverse effects. Drugs whose toxicity is not reversed by adenine and hypoxanthine and which demonstrate reduction of incorporation into nucleotides of both formate and hypoxanthine are sub-divided into 4 categories. The first 2 inhibit macro-molecule synthesis with differences in drug nucleotide formation and cell volume. The latter 2 categories form drug nucleotides and show diverse effects on ribonucleotide pools and DNA, RNA and protein synthesis. Five groups remain. One markedly inhibits DNA synthesis, a 2nd involves IMP dehydrogenase inhibition, and a 3rd shows high GTP levels and marked reduction of formate and hypoxanthine incorporation. The last 2 groups, involving potentiation by deoxycoformycin or guanine, overlap with the groups already discussed. This study directs attention to promising analogs which warrant further biochemical and pharmacological investigation and perhaps clinical trial.