title: Time-dependent thermocontrol of the hydrophilic and lipophilic properties of DNA oligonucleotide prodrugs.
abstract: This unit describes the preparation of alkylthioalkylated and formamidoalkylated alcohols, an amidoalkylated alcohol, a hydroxylalkylated phosphoramidate, and their phosphoramidothioate derivatives, all of which have been identified as heat-sensitive thiophosphate-protecting groups in the development of thermolytic immunostimulatory DNA prodrugs. The alcohols are converted to their deoxyribonucleoside phosphoramidite derivatives, which are then used in the preparation of thermosensitive dinucleoside phosphorothioates. The thiophosphate-protecting groups of these dinucleoside phosphorothioates presumably undergo thermolytic cyclodeesterification at elevated temperature under essentially neutral conditions to release the desired phosphorothioate diester function. On the basis of their thermolytic deprotection kinetics, one can identify those thiophosphate-protecting groups that (i) may be useful for thiophosphate protection of CpG motifs of immunostimulatory DNA oligonucleotides (CpG ODNs); (ii) are suitable for protection of phosphodiester functions flanking the CpG motifs; and (iii) offer adequate protection of terminal phosphodiester functions against ubiquitous extracellular and intracellular exonucleases that may be found in biological environments.
authors.affiliation: Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ausín
authors.forename: Andrzej
authors.initials: A
authors.lastname: Grajkowski
authors.forename: Jacek
authors.initials: J
authors.lastname: Cieślak
authors.forename: Alexei
authors.initials: A
authors.lastname: Gapeev
authors.forename: Serge L
authors.initials: SL
authors.lastname: Beaucage
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics
chemical_list: D000276:Adjuvants, Immunologic; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D011355:Prodrugs; D004247:DNA