Synthesis of Three‐Dimensional (Di)Azatricyclododecene Scaffold and Its Application to Peptidomimetics

A novel sp3 carbon‐rich tricyclic 3D scaffold‐based peptide mimetic compound library was constructed to target protein‐protein interactions. Tricyclic framework 7 was synthesized from 9‐azabicyclo[3,3,1]nonan‐3‐one (11) via a gold(I)‐catalyzed Conia‐ene reaction. The electron‐donating group on the pendant alkyne of cyclization precursor 12 b–e was the key to forming 6‐endo‐dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D‐scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a–u were synthesized via step‐by‐step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a–h were synthesized as α‐helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell‐based assays: antiproliferative activity, HIF‐1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF‐1 transcriptional activity (IC50=4.1±0.8 μM), whereas compounds 21 a–g showed antiviral activity with IC50 values of 4.2–12.4 μM, suggesting that the 3D‐scaffold 8 a has potential as a versatile peptide mimic skeleton. Three‐dimensional (3D) scaffolds have the potential to provide unique bioactivity, which cannot be achieved by conventional flat aromatic ring‐based compounds. (Di)Azatricyclododecene scaffold with a bridged tricyclic system was developed and applied to design peptidomimetics with a 3D scaffold. The designed peptidomimetics showed inhibition of HIF transcription activity and antiviral activity toward rabies virus, both of which α‐helix peptide mediated interaction play a pivotal role.