Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity

  • Bioorg Med Chem. 2022 Jul 15;66:116820. doi: 10.1016/j.bmc.2022.116820.
Shuhei Kawamura  1 ,  Rachel L Palte  2 ,  Hai-Young Kim  3 ,  Josep Saurí  3 ,  Christopher Sondey  4 ,  My S Mansueto  4 ,  Michael D Altman  2 ,  Michelle R Machacek  5
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, United States. Electronic address: [email protected].
  • 2. Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • 3. NMR Structure Elucidation, Process and Analytical Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • 4. Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115, United States.
  • 5. Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
PMID: 35594650 DOI: 10.1016/j.bmc.2022.116820
Abstract

Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5'-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.

Keywords
Cyclonucleoside; Medicinal chemistry; Molecular modeling; Nucleoside; PRMT5; PRMT5 inhibitor; X-ray crystallography.
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