Synthesis and biological evaluation of novel pyrimidine nucleoside analogues of 1,4-oxathiane, 1,4-dithiane, and 1,4-dioxane.
Nine pyrimidine nucleoside analogues, in which the group attached at N-1 is a six-membered ring containing two heteroatoms, have been synthesized using the Vorbrüggen and Bennua (Vorbrüggen, H.; Bennua, B. Tetrahedron Lett. 1978, 1339) coupling procedure. These are 1-(1,4-oxathian-3-yl)-5-fluorouracil (8), 1-(4-oxo-1,4-oxathian-3-yl)-5-fluorouracil (two stereoisomers 9 and 10, resolved by silica gel column chromatography, 1-(1,4-oxathian-3-yl)-5-fluorouracil (11), 1-(1,4-oxathian-2-yl)-5-fluorouracil (12), 1-(1,4-dithin-2-yl)-5-flourouracil (15), 1-(1,4-dithian-2-yl)uracil (16), 1-(1,4-dithian-2-yl)thymine (17), and 1-(1,4-dioxan-2-yl)-5-fluorouracil (20). All of the analogous were tested for cell-growth inhibition using mouse and human tumor cell lines. The ID50 values of all of the analogues  are greater than 10(-4) M, except in the case of 11 using the L1210 cell line. The most active analogues found are compounds 11 and 17, which were found to be 100 and 200 times less active, respectively, than 5-fluorouracil in the human erythroleukemia cell line, K-562.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D005472:Fluorouracil / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D011741:Pyrimidine Nucleosides; D005472:Fluorouracil