Conformationally Controlled sp3‐Hydrocarbon‐Based α‐Helix Mimetics

With over 60% of protein–protein interfaces featuring an α-helix, α-helix mimetics as inhibitors of these biomolecular interactions is a prevalent therapeutic strategy. However, methods to control the conformation of mimetics, thus enabling maximum efficacy, such as backbone stapling, can be restrictive. Alternatively, conformation can be controlled through the introduction of destabilizing interactions, such as the syn-pentane interaction. This tactic, which is often adopted by Nature, is not a common feature of lead optimization, presumably owing to the significant synthetic effort required. Through assembly-line synthesis with NMR and computational analysis, we have designed, prepared and characterized alternating syn–anti configured contiguously substituted hydrocarbons, which, through the avoidance of syn-pentane interactions, adopt well-defined conformations that present functional groups in an arrangement that mimics the α-helix. The design of a p53 mimetic, which binds to Mdm2 with moderate to good affinity, demonstrates the therapeutic promise of these scaffolds.