Synthetic α-helix mimetics that can be functionalized on both “faces” might provide higher affinity and/or selectivity for their intended biological targets. Alternatively, the addition of functionality to a second “face” could serve as a solubilizing group. Recently, we introduced 1,2-diphenylacetylenes as amphipathic α-helix mimetics. Herein, we describe a new class of amphipathic α-helix mimetics based on a 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine scaffold. Due to their fixed locations in the diazepine ring, substitution of both nitrogens permits good spatial mimicry of the i and i + 2 side chains found on opposing faces of an α-helix. As proof-of-principle of our design, we have successfully designed inhibitors of the Mcl-1 oncoprotein through mimicry of the amphipathic, α-helical BH3 domain of its native partner protein Bim.

Amphipathic α-helix mimetics based on a 1,4-disubstituted 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine: Inhibition of the Mcl-1 oncoprotein

249th National Meeting (2015)

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