Reactive 5'-substituted thymidine derivatives as potential inhibitors of nucleotide biosynthesis.
Fourteen derivatives of thymidine substituted at the 5'-position with haloacetamido (2-4), 2- and 3-bromopropionamido (5 and 6), bromoacetoxy (7), O-mesylglycolamido (8), bromo- and chloro-N-methylacetamido (10 and 11), bromomethanesulfonamido (12), ethyloxamido (13), 4- and 3-(fluorosulfonyl)benzamido (14 and 15), and (phenoxycarbonyl)amino (16) groups have been synthesized and evaluated as potential inhibitors of enzymes that metabolize purine and pyrimidine nucleosides. Rates of reaction of these nucleosides with mercaptoethanol at pH 7 were compared and related to biological activity. Compounds 2, 3, and 7 were cytotoxic to H.Ep.-2 and L1210 cells in culture and 5'-(bromo- and iodoacetamido)-5'-deoxythymidine (2 and 3) showed good activity against P388 leukemia in mice.
R D
RD
Elliott
R W
RW
Brockman
J A
JA
Montgomery
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006207:Half-Life; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides / Q000096:biosynthesis*; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides; D012313:RNA; D004247:DNA; D013936:Thymidine