title: Enhancement of nucleoside cytotoxicity through nucleotide prodrugs.
abstract: A common reason for the lack of cytotoxicity of certain nucleosides is thought to be their inability to be initially activated to the monophosphate level by a nucleoside kinase or other activating enzyme. In a search for other nucleosides that might be worthwhile anticancer agents, we have begun to examine the utilization of monophosphate prodrugs in order to explore whether any enhanced cytotoxicity might be found for the prodrugs of candidate nucleosides that have little or no cytotoxicity. To that end, 5'-bis(pivaloyloxymethyl) phosphate prodrugs of two weakly cytotoxic compounds, 8-aza-2'-deoxyadenosine (5) and 8-bromo-2'-deoxyadenosine (9), have been prepared. These prodrugs (8 and 12) were examined for their cytotoxicity in CEM cells and were found to possess significantly enhanced cytotoxicity when compared with the corresponding parent nucleosides. Further cell culture experiments were conducted to gain insight into the mechanisms of cytotoxicity of these two prodrugs, and those data are reported.
authors.affiliation: Southern Research Institute, P.O. Box 55305, Birmingham, Alabama 35255-5305, USA.
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Rose
authors.forename: William B
authors.initials: WB
authors.lastname: Parker
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Someya
authors.forename: Sue C
authors.initials: SC
authors.lastname: Shaddix
authors.forename: John A
authors.initials: JA
authors.lastname: Montgomery
authors.forename: John A
authors.initials: JA
authors.lastname: Secrist
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004256:DNA Polymerase I / Q000737:chemistry; D003839:Deoxyadenosines / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014541:Uridine Kinase / Q000378:metabolism
chemical_list: C466641:8-aza-2'-deoxyadenosine; D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D011355:Prodrugs; C466642:bis(pivaloyloxymethyl) 8-aza-2'-deoxyadenosine-5'-monophosphate; C466643:bis(pivaloyloxymethyl) 8-bromo-2'-adenosine-5'-monophosphate; C042464:8-bromo-2'-deoxyadenosine; D000249:Adenosine Monophosphate; D012313:RNA; D004247:DNA; D014541:Uridine Kinase; D004256:DNA Polymerase I