Design and Synthesis of Novel Amphiphilic α-Helix Mimetics Based on a New Tris-Benzamide Scaffold

摘要

As the most abundant structural motif in proteins, an a-helix often involves in the formation of protein complexes. To modulate such protein-protein interaction, a-helix mimetics have been designed by using rigid and pre-organized scaffolds with low molecular weights and high synthetic efficiency. During the past decade, a handful of a-helix mimetics were reported including terphenyls [1], trispyridylamides [21, polycyclic ethers [31, pyridazines [41, and tris benzamides [5]. However, all of them focus on representing only one side of an a-helix organized by side chains at the i, i+3/i+4 and i+7 positions. Compared to these "one-sided" α-helix mimetics, engineering a molecule to mimic two opposing helical faces is still a formidable task. Amphiphilic αhelix mimetics that present side chains from both hydrophobic and hydrophilic surfaces of a helix, will strongly interact with target proteins, which in turn leads to high binding affinity and potent biological activity. Thus, we have designed new amphiphilic ahelix mimetics by using our recently developed trisbenzamide scaffold [5] as a template due to its high structural rigidity, synthetic efficiency, and easy derivatization (Figure 1). The new scaffold places five side-chain functionalities, three found at the i, i+3/i+4, i+7 positions on one helical face and two at the i+2, i+5 positions on the opposite side.