title: Solid-phase synthesis of thermolytic DNA oligonucleotides functionalized with a single 4-hydroxy-1-butyl or 4-phosphato-/thiophosphato-1-butyl thiophosphate protecting group.
abstract: Several thermolytic CpG-containing DNA oligonucleotides analogous to 1 have been synthesized to serve as potential immunotherapeutic oligonucleotide prodrug formulations for the treatment of infectious diseases in animal models. Specifically, the CpG motif (GACGTT) of each DNA oligonucleotide has been functionalized with either the thermolabile 4-hydroxy-1-butyl or the 4-phosphato-/thiophosphato-1-butyl thiophosphate protecting group. This functionalization was achieved through incorporation of activated deoxyribonucleoside phosphoramidite 8b into the oligonucleotide chain during solid-phase synthesis and, optionally, through subsequent phosphorylation effected by phosphoramidite 9. Complete conversion of CpG ODNs hbu1555, psb1555, and pob1555 to CpG ODN 1555 (homologous to 2) occurred under elevated temperature conditions, thereby validating the function of these diastereomeric oligonucleotides as prodrugs in vitro. Noteworthy is the significant increase in solubility of CpG ODN psb1555 and CpG pob1555 in water when compared to that of neutral CpG ODN fma1555 (homologous to 1).
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Grajkowski
authors.forename: Cristina
authors.initials: C
authors.lastname: Ausín
authors.forename: Jon S
authors.initials: JS
authors.lastname: Kauffman
authors.forename: John
authors.initials: J
authors.lastname: Snyder
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.forename: John R
authors.initials: JR
authors.lastname: Lloyd
authors.forename: Serge L
authors.initials: SL
authors.lastname: Beaucage
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000627:therapeutic use; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D008956:Models, Chemical; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000737:chemistry; D063086:Organothiophosphates / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000627:therapeutic use; D013237:Stereoisomerism; D013873:Thionucleotides / Q000737:chemistry
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D063086:Organothiophosphates; D011355:Prodrugs; D013873:Thionucleotides; C434331:phosphoramidite; D004247:DNA