title: Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity.
abstract: We report the synthesis of a family of D- and L-furano-D-apionucleosides, their 3'-deoxy, as well as their 2',3'-dideoxy analogues with thymine and adenine nucleobases. Single carbon homologation of 1,2-O-isopropylidene-D-glycero-tetrafuranos-3-ulose (15) and optimized glycosylation conditions involving microwave irradiation were key to the successful synthesis of the target compounds. While all target nucleosides failed to show significant antiviral activity, we demonstrated that the triphosphate of 2',3'-deoxy-D-apio-D-furanoadenosine (1), in contrast to that of its D-apio-L-furanose epimer 2, was readily incorporated into a DNA template by HIV reverse transcriptase to act as a DNA chain terminator. This led us to convert adenine derivative 1 into two phosphoramidate prodrugs. ProTide 9b was found active against HIV-1 and HIV-2 (EC50 = 0.5-1.5 μM), indicating that the lack of activity of the parent nucleoside, and possibly also other members of the D-apio-D-furanose nucleoside family must be sought in the inefficient cellular conversion to the monophosphate.
authors.affiliation: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University , Harelbekestraat 72, B-9000 Ghent, Belgium.
authors.forename: Kiran S
authors.initials: KS
authors.lastname: Toti
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.forename: Davy
authors.initials: D
authors.lastname: Sinnaeve
authors.forename: Freya
authors.initials: F
authors.lastname: Van den Broeck
authors.forename: Lia
authors.initials: L
authors.lastname: Margamuljana
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006031:Glycosylation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C000594691:1,2-O-isopropylidene-D-glycero-tetrafuranos-3-ulose; C000594692:2',3'-deoxy-D-apio-D-furanoadenosine; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D015224:Dideoxynucleosides; D009844:Oligosaccharides; D010755:Organophosphates; D011355:Prodrugs; D004247:DNA; D054303:HIV Reverse Transcriptase; D005990:Glycerol