Abstract
α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.
Highlights
We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using ‘click’ chemistry
A variety of commercially available azides were chosen; a protected acid, methyl 2-azidoacetate, and an ethylene glycol, O-(2-azidoethyl)-O′-methyl-triethylene glycol in order to synthesise a trimer related to the ‘wet-edge’ foldamer described previously.[39]
The analysis shows that in the case of functionalised trimers 2 and 3 there are additional energetic barriers to rotation about the central N-aryl bond. These higher energy conformations result from a steric clash between the O-alkyl group and carbonyl group on the adjacent aromatic ring (Fig. 4d) and may diminish the ability of the helix mimetic to adopt a conformation in which the α-helix mimicking side chains are aligned on one face
Summary
We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using ‘click’ chemistry. We describe a strategy to achieve such a goal, through functionalisation of the non-helix mimicking face of N-alkylated aromatic oligoamides (Fig. 1c), by ‘click’ chemistry. Our group has targeted the p53/hDM2 interaction using both N- and O-alkylated aromatic oligoamide helix-mimetics (Fig. 1c and d).[31,32,33] To improve the solubility of the O-alkylated series an ethylene glycol chain was introduced onto the non-binding face,[39] which improved aqueous solubility without abrogating. The synthesis of this modified O-alkylated helix mimetic proved challenging and informed our strategy in the current work; we decided to combine features of both scaffolds; the N-alkylated scaffold to display the binding groups and the O-alkyl function to install a ‘click’ chemistry functional handle. 13 ± 4 μMa a Kd obtained through direct titration
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