Inhibitors of nucleoside transport. A structure-activity study using human erythrocytes.
The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-beta-D-ribofuranosylpurine (1) with S, O, 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 synthesis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10(-5)-10(-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 reduced inhibitory activity, compounds with 9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl)thio] derivatives of 1 were the most potent of the inhibitors tested, being active at about 10(-7) M.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002854:Chromatography, Paper; D003864:Depression, Chemical; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000494:pharmacology; D009705:Nucleosides / Q000097:blood*; D011684:Purine Nucleosides / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013866:Thioguanine / Q000031:analogs & derivatives / Q000494:pharmacology
D009705:Nucleosides; D011684:Purine Nucleosides; D007288:Inosine; D015122:Mercaptopurine; D013866:Thioguanine; D000241:Adenosine