Reference

Effects of 2',3'-dideoxynucleosides on mammalian cells and viruses

Effects of 2',3'-dideoxynucleosides on mammalian cells and viruses. Waqar, M. Anwar; Evans, Mary Jo; Manly, Kenneth F.; Hughes, Robert G.; Huberman, Joel A. (Dep. Cell Tumor Biol., Roswell Park Mem. Inst., Buffalo, NY 14263, USA). J. Cell. Physiol., 121(2), 402-8 (English) 1984. CODEN: JCLLAX. ISSN: 0021-9541. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The 2',3'-dideoxynucleosides (ddNs) 5'-triphosphates ddATP [24027-80-3], ddCTP [66004-77-1], and ddGTP [68726-28-3] were shown to affect cellular DNA polymerases a, b, and g in the same fashion as does ddTTP [611-60-9]. All 4 resp. ddNs in concns. up to 100 mM had negligible effects on the growth of NIH Swiss 3T3 cells. These negligible effects may be due to inefficient intracellular phosphorylation of each nucleoside to the triphosphate. It was detd. that, in several different cell lines, ddThd [3416-05-5] is phosphorylated only at a very slow rate to ddTTP, and in the one cell line tested (monkey CV-1 cells), ddAdo [4097-22-7] and ddGuo [85326-06-3] were also poorly phosporylated. Both ddAdo and ddGuo, and probably ddThd, are converted by CV-1 cells to addnl. unknown compds. which may have biol. activity. The 4 ddNs display effects of different magnitudes on certain virus infections. Although 30 mM ddThd inhibits herpes simplex I infection of CV-1 cells by 50%, 30 mM ddAdo has no effect. Infection of NIH Swiss 3T3 cells by 334C murine leukemia virus is inhibited 70-80% by ddAdo, ddCyd [7481-89-2] and ddThd at 50 mM, but inhibition by 50 mM ddGuo is 100%.

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

Structural modifications at the 2'- and 3'- positions of some pyrimidine nucleosides as determinants of their interaction with the mouse erythrocyte nucleoside transporter. Gati, Wendy P.; Misra, Hemant K.; Knaus, Edward E.; Wiebe, Leonard I. (Fac. Pharm. Pharm. Sci., Univ. Alberta, Edmonton, AB T6G 2N8, Can.). Biochem. Pharmacol., 33(21), 3325-31 (English) 1984. CODEN: BCPCA6. ISSN: 0006-2952. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) A no. of synthetic uracil and thymine nucleosides which differ from the physiol. nucleosides, uridine [58-96-8], deoxyuridine [951-78-0] and thymidine [50-89-5], through structural changes at the 2'- and 3'-positions were studied. Interaction of the analogs with the transporter was 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-(b-D-Arabinofuranosyl)uracil (araU) [3083-77-0] and 1-(b-D-arabinofuranosyl)thymine (araT) [605-23-2] 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 [19325-94-1] weakly accelerated thymidine efflux while its ribo-isomer and the other 3'-halogeno-3'-deoxyarabino analogs as well as dideoxythymidine [3416-05-5] inhibited efflux. The absence of 2'- and 3'-carbons in acyclothymidine [68724-11-8] and acyclouridine [78097-04-8] strongly decreased the affinities of these nucleosides for the transporter; efflux of thymidine was not accelerated in the presence of these compds. The conformationally constrained cyclic nucleoside 2,2'-anhydro-araU [3736-77-4] had a very low affinity for the transporter, and influx of the radiolabeled compd. 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 detg. nucleoside conformation should be considered in assessing structural requirements for permeants of the transporter.