The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-dD-ribofuranosylpurine (1) with S, 0, or N atoms at the purine 6 position bearing variously substituted arylalkyl groups. In this structure-activity study, nucleoside derivatives were compared in respect to their ability to inhibit a transport-dependent aspect of nucleoside metabolism in erythrocytes, the synthe-sis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10_5-X0-6 M and the similarity of their activities suggested that alkylation of the transporter as the mechanism of transport inhibition was unlikely. The hydrophobicity of the 6-position substituents appeared to contribute importantly to inhibitory activity. Although replacement of the ribofuranose moiety by other sugars re-duced inhibitory activity, compounds with9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl) thio] deriva-tives of 1 were the most potent of the inhibitors tested, being active at about 10-7 M.

Nucleoside permeation in erythrocytes1" 4 and in various other cell types5" 9 has been recognized as a process mediat-ed by transport elements of the plasma membrane. Studies in this laboratory have demonstrated that uridine trans-port by human erythrocytes is a “facilitated diffusion” pro-cess. 1· 3'4 The uridine transport mechanism of the erythro-cyte is of broad specificity in that it accepts as “substrates” ribosyl and deoxyribosyl derivatives of both purines and pyrimidines. 1· 3· 4