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

A novel sp 3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. T ricyclic framework 6 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one 9 via a gold (I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 11b-e was the key to forming 6- endo - dig cyclized product 6 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 6 , a diazatricyclododecene 3D-scaffold 7a , which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 20a-h were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 7a . C o mpounds 20a-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 20a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC 50 = 4.1 ± 0.8 μM), whereas compounds 20a-g showed antiviral activity with IC 50 values of 4.2-12.4 μM, suggesting that the 3D-scaffold 7a has potential as a versatile peptide mimic skeleton.