Several antimetabolites have been demonstrated to have the capacity to initiate differentiation in vitro of a variety of leukemic cell lines. To explore the structural requirements for this activity, a series of purine and 8-substituted purine arabinofuranosyl and ribofuranosyl nucleoside derivatives were synthesized and tested as inducers of the differentiation of Friend murine erythroleukemia cells. 9-(beta-D-Arabinofuranosyl)hypoxanthine and 6-(hydroxyamino)-9-(beta-D-arabinofuranosyl)purine were effective inducers of maturation, producing 82% and 74% benzidine-positive cells, a measure of the number of cells synthesizing hemoglobin. 6-Mercapto-9-(beta-D-ribofuranosyl)purine and 6-(methylmercapto)-9-(beta-D-ribofuranosyl)purine and their corresponding beta-D-arabinofuranosyl derivatives were also effective initiators of maturation, causing approximately 50% of the cell population to assume a differentiated phenotype.