Structural modifications at the 2'— and 3'— positions of some pyrimidine nucleosides as determinants of their interaction with the mouse erythrocyte nucleoside transporter

Abstract

Modifications in the sugar moiety of pyrimidine nucleosides may affect their ability to function as permeants of the mouse erythrocyte nucleoside transporter. In this investigation, a number of synthetic uracil and thymine nucleosides which differ from the physiological nucleosides, uridine, deoxyuridine and thymidine, through structural changes at the 2′- and 3′-positions were studied. Interaction of the analogs with the transporter has been assessed in terms of their affinities for an external site on the transporter as well as their abilities to effect trans-acceleration of thymidine efflux. 1-(β- D-Arabinofuranosyl) uracil (araU) and 1-(β- D-arabinofuranosyl)thymine (araT) were comparable to thymidine as permeants while nucleosides in which the 3′-hydroxyl was replaced with hydrogen or a halogen had a decreased affinity for the transporter. 3′-Fluoro-3′-deoxy-araU weakly accelerated thymidine efflux while its ribo-isomer and the other 3′-halogeno-3′deoxy-arabino analogs as well as dideoxythymidine inhibited efflux. The absence of 2′- and 3′-carbons in acyclothymidine and acyclo-uridine strongly decreased the affinities of these nucleosides for the transporter; efflux of thymidine was not accelerated in the presence of these compounds. The conformationally constrained cyclic nucleoside 2,2′-anhydro-araU had a very low affinity for the transporter, and influx of the radiolabeled compound could not be demonstrated. The results suggest that modification at the 3′-position, loss of a portion of the sugar ring, and lack of conformational flexibility are factors which decrease the abilities of some pyrimidine nucleosides to function as permeants. It is suggested that combined effects of substituents which play a role in determining nucleoside conformation should be considered in assessing structural requirements for permeants of the transporter.