DREAMY · Disrupting Aberrant Protein–Protein Interactions with Conformationally Constrained Hydrocarbon α-Helical Mimetics

Disrupting Aberrant Protein–Protein Interactions with Conformationally Constrained Hydrocarbon α-Helical Mimetics

Overall assessment: The project has achieved most of its objectives and milestones for the period, with relatively minor deviations. It is well known that the conformation of a molecule is often critical to its desired function. This is especially true for drug molecules that typically need to access a particular conformation in order to preferentially interact with its receptor. The pharmaceutical industry has stereotypically focused its attention on small, heterocyclic rigid molecules that do not have complicated conformational landscapes. However, in recent years more complex receptors, with large binding domains, have come to the attention of pharmaceutical scientists and the traditional small rigid molecules are inadequate at targeting such large receptors. Therefore, there has been increased interest in the design, synthesis, and analysis of conformationally constrained molecules to target large binding sites. A classic example is the design of α-helix mimetics that can target aberrant protein-protein interactions. Controlling molecular conformation is not limited to the introduction of intramolecular interactions within a molecule. Introducing destabilizing interactions, such as the syn-pentane interaction, has also been shown to be effective at controlling molecular conformation. The host laboratory has successfully introduced destabilizing interactions such as the syn-pentane interactions and created an organic molecule with tailored shapes. According to the host group, substituted carbon chains can be grown one carbon atom at a time with exquisite control of relative and absolute configuration through iterative homologation of boronic esters with stereochemically-defined lithiated carbamates or benzoates. When a boronic ester is treated with a lithiated carbamate or benzoate, a boronate complex is formed which upon warming undergoes 1,2-migration—the organic group on boron migrates to the neighboring carbon atom with the expulsion of the carbamate or benzoate—giving a new boronic ester, a one-carbon-extended version of the starting boronic ester. This process can be repeated with the newly formed boronic ester, either by using the same or the opposite enantiomer of the lithiated benzoate/carbamate or indeed a differently substituted benzoate/carbamate. It was also realized that depending on the relationship between the methyl groups of a fully methylated hydrocarbon, specific conformations of the backbone would be adopted to avoid destabilizing syn-pentane interactions. All-syn contiguously methyl-substituted hydrocarbons will adopt alternating g+/- t (±60°, 180°) dihedral angles, resulting in a helical conformation whilst alternating syn-anti substitution patterns will adopt t dihedral angles, resulting in a linear conformation. It was recognized that for both the linear and helical structures the distance between the side chains that are on the same face of the linear or helical backbone closely resembles the distance between residues on one face of an α-helix. For the linear structure, distances of ~5.3 Å are observed and for the helical structure distances of ~6.5 Å are observed. Comparing this to the distances between residues in an α-helix (5-7 Å), we propose that the linear and helical scaffolds would make suitable α-helical mimetics (Picture1).

Data: CORDIS, © European Union