title: Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis.
abstract: Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.
authors.affiliation: Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255.
authors.forename: R D
authors.initials: RD
authors.lastname: Elliott
authors.forename: H J
authors.initials: HJ
authors.lastname: Thomas
authors.forename: S C
authors.initials: SC
authors.lastname: Shaddix
authors.forename: D J
authors.initials: DJ
authors.lastname: Adamson
authors.forename: R W
authors.initials: RW
authors.lastname: Brockman
authors.forename: J M
authors.initials: JM
authors.lastname: Riordan
authors.forename: J A
authors.initials: JA
authors.lastname: Montgomery
mesh_terms: D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004355:Drug Stability; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000378:metabolism; D008130:Lomustine / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D009711:Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D007202:Indicators and Reagents; D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D009705:Nucleosides; D009711:Nucleotides; D008130:Lomustine; D002330:Carmustine