title: Phosphoroselenoate oligodeoxynucleotides: synthesis, physico-chemical characterization, anti-sense inhibitory properties and anti-HIV activity.
abstract: Oligodeoxynucleotides with a phosphorus atom in which one of the non-bridging oxygen atoms is substituted by selenium were prepared and investigated with respect to their antisense properties. A general synthesis of phosphoroselenoate analogs of oligonucleotides is described using potassium selenocyanate as the selenium donor. The compounds, characterized by 31P NMR, were shown to decompose to phosphate with a half-life of ca. 30 days. Melting temperatures of duplexes between poly(rA) or poly(rI) with oligo(dT) and oligo(dC), respectively, indicate diminished hybridization capability of phosphoroselenoate oligomers relative to both the unmodified phosphodiester oligomers and the phosphorothioate congeners. A phosphoroselenoate 17-mer is a sequence specific inhibitor of rabbit beta-globin synthesis in wheat germ extract and in injected Xenopus oocytes. In contrast phosphoroselenoate analogs are potent non-sequence specific inhibitors in rabbit reticulocyte lysate. In vitro HIV assays were carried out on a phosphoroselenoate sequence and compared with a phosphorothioate analogue that has previously been shown to exhibit anti-HIV activity (Matsukura et al., Proc. Natl. Acad. Sci. (1987) 84, 7706-7710). The phosphoroselenoate was somewhat less active, and was much more toxic to the cells.
authors.affiliation: Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.forename: C
authors.initials: C
authors.lastname: Boiziau
authors.forename: C
authors.initials: C
authors.lastname: Cazenave
authors.forename: M
authors.initials: M
authors.lastname: Matsukura
authors.forename: C
authors.initials: C
authors.lastname: Subasinghe
authors.forename: J S
authors.initials: JS
authors.lastname: Cohen
authors.forename: S
authors.initials: S
authors.lastname: Broder
authors.forename: J J
authors.initials: JJ
authors.lastname: Toulmé
authors.forename: C A
authors.initials: CA
authors.lastname: Stein
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001483:Base Sequence; D004247:DNA; D016373:DNA, Antisense; D005260:Female; D005914:Globins / Q000235:genetics; D006678:HIV / Q000187:drug effects*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010944:Plants / Q000378:metabolism; D011131:Polyribonucleotides; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics*; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D012643:Selenium / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D000998:Antiviral Agents; D016373:DNA, Antisense; D007202:Indicators and Reagents; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D011131:Polyribonucleotides; D012333:RNA, Messenger; D005914:Globins; D004247:DNA; D012643:Selenium