Synthesis of C-4'truncated phosphonated carbocyclic 2'-oxa-3'-azanucleosides as antiviral agents.
A new template of C-4'-truncated phosphonated nucleosides (TPCOANs) has been obtained in good yields according to two different routes which exploit the reactivity of a phosphonated nitrone. The one-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl nucleobases leads to the unnatural alpha-nucleosides as the main adducts. On the other hand, the target beta-anomers have been obtained in high yield by a two-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl acetate followed by nucleosidation reaction. The reactivity of the phosphonated nitrone has been investigated trough quantum mechanical DFT calculations at the B3LYP/D95+(d,p) theory level. Preliminary biological assays show that beta-anomers of TPCOANs are able to inhibit the reverse transcriptase of different retroviruses at concentrations in the nanomolar range, with a potency comparable with that of tenofovir.
Piperno
Anna
A
Dipartimento Farmaco-Chimico, University of Messina, Via SS. Annunziata, Messina 98168, Italy. apiperno@pharma.unime.it
Giofrè
Salvatore V
SV
Iannazzo
Daniela
D
Romeo
Roberto
R
Romeo
Giovanni
G
Chiacchio
Ugo
U
Rescifina
Antonio
A
Piotrowska
Dorota G
DG
D000146:Acids, Carbocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003500:Cyclization; D006801:Humans; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000138:chemical synthesis; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011789:Quantum Theory; D012190:Retroviridae / Q000187:drug effects / Q000201:enzymology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014753:Vinyl Compounds / Q000138:chemical synthesis
D000146:Acids, Carbocyclic; D001372:Aza Compounds; D009589:Nitrogen Oxides; D009705:Nucleosides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D014753:Vinyl Compounds; C015388:nitrones; C011566:vinyl acetate