Retro-1-Oligonucleotide Conjugates. Synthesis and Biological Evaluation
Jordi Agramunt,
Enrique Pedroso,
Silvia M. Kreda,
Rudolph L. Juliano,
Anna Grandas
Affiliations
Jordi Agramunt
Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and IBUB, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Enrique Pedroso
Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and IBUB, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Silvia M. Kreda
UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27516, USA
Rudolph L. Juliano
UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
Anna Grandas
Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and IBUB, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently linking Retro-1 to the biologically active oligonucleotide, three different derivatives of Retro-1 were prepared that incorporated a phosphoramidite group, a thiol or a 1,3-diene, respectively. Retro-1⁻oligonucleotide conjugates were assembled both on-resin (coupling of the phosphoramidite) and from reactions in solution (Michael-type thiol-maleimide reaction and Diels-Alder cycloaddition). Splice switching assays with the resulting conjugates showed that they were active but that they provided little advantage over the unconjugated oligonucleotide in the well-known HeLa Luc705 reporter system.
