α-Helix is the most common structural motif in proteins and frequently plays an important role in protein-protein interactions [1,2]. Thus, small molecules that can modulate this fundamental process would be of great value in studying numerous key biochemical pathways. Whereas short peptide fragments derived from helical segments in proteins have been employed to regulate protein complex formations, their effective use has been limited by high conformational flexibility in solution, rapid enzymatic degradation, and difficulty in penetrating membrane. To overcome these issues, non-peptidic a-helix mimetics have been developed by using rigid and pre-organized scaffolds to interact with target proteins [2-7]. Although rational design of a-helix mimetics has been successful in modulating protein-protein interaction, it is still difficult to arrange all functional groups of a-helix mimetics as accurately as found in an ideal a-helix. Therefore, it is often necessary to produce a number of analogues for rapid identification of initial leads with high biological activity. Recently, we have designed a trisbenzamide scaffold to present side chain functional groups found at the i, i+4, and i+7 positions in a helix [7], and report herein an efficient solid-phase synthetic strategy to construct a library of tris-benzamides.
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