Synthesis and Biophysical Studies of High-Affinity Morpholino Oligomers Containing G-Clamp Analogs

  • J Org Chem. 2023 Nov 3;88(21):15168-15175. doi: 10.1021/acs.joc.3c01658.
Arnab Das  1 ,  Atanu Ghosh  1 ,  Jayanta Kundu  2 ,  Martin Egli  3 ,  Muthiah Manoharan  2 ,  Surajit Sinha  1
Affiliations
  • 1. School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.
  • 2. Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, United States.
  • 3. Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 37843026 DOI: 10.1021/acs.joc.3c01658
Abstract

Successful syntheses of chlorophosphoramidate morpholino monomers containing tricyclic cytosine analogs phenoxazine, G-clamp, and G8AE-clamp were accomplished. These modified monomers were incorporated into 12-mer oligonucleotides using trityl-chemistry by an automated synthesizer. The resulting phosphorodiamidate morpholino oligomers, containing a single G-clamp, demonstrated notably higher affinity for complementary RNA and DNA compared to the unmodified oligomers under neutral and acidic conditions. The duplexes of RNA and DNA with G-clamp-modified oligomers adopt a B-type helical conformation, as evidenced by CD-spectra and show excellent base recognition properties. Binding affinities were sequence and position dependent.

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