- Ni-to-Ni + 3-ethylene-bridged partially modified retro-inverso tetrapeptide β-turn mimetic: Design, synthesis, and structural characterizationt
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A 10-membered heterocyclic ring system 1,3,8-trisubstituted 2,5,7-trioxo-1,4,8-triazadecane that represents a Ni-to-Ni + 3-ethylene-bridged partially modified retro-inverso tetrapeptide β-turn mimetic (EBRIT-BTM) has been designed, synthesized, and structurally analyzed. These compounds utilize an ethylene bridge to replace the COi · · · HNi + 3 10-membered hydrogen bond of standard β-turns. The N, N'-ethylene-bridged dimer was obtained in 90% yield by reductive alkylation of phenylalanylamide with a tert-butyl N-(9-fluorenylmethyloxycarbonyl), N-(2-formylmethyl)-glycinate. An orthogonal protection strategy and HATU-mediated couplings allowed efficient stepwise additions of monomeric building blocks leading to a Ni-to-Ni+3-ethylene-bridged linear precursor: H-Asp-(OcHex)-NGly-OBut HO2CCH2CO-NPhe-NH2. Further elaboration of the linear precursor generated the ethylene-bridged model compounds H2N-rPheN-mGly-Asp-NGly-OH (16) and Ac-gPheN-mGly-Asp-NGly-OH (18) (g, gem-diaminoalkyl; m, malonyl; and r, direction-reversed amino acid residue) in 44 and 39% yields, respectively. The structural features of the two EBRIT-BTM compounds were determined using 1H NMR and extensive computer simulations. The results indicate that the 10-membered rings are conformationally constrained with well-defined structural features and that the three amide bonds in the ring are in the trans orientation. The topological arrangement of the residues in the ring system closely resembles a type II' β-turn. Transformation of CONH2 in the N-terminal amino acid residue of 16 into NHCOCH3 in 18 resulted in the formation of a hydrogen bond between the NH ofgPhe-COCH3 and the C-terminal carboxyl of Gly, initiating an antiparallel β-sheet. The formulation of the concept applying a minimalistic structural elaboration approach and the synthetic exploration, together with the conformational analysis, offer a new molecular scaffolding system and a true tetrapeptide secondary structure mimetic that can be used to generate peptidomimetics of biological interest.
- Han, Yinglin,Giragossian, Craig,Mierke, Dale F.,Chorev, Michael
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p. 5085 - 5097
(2007/10/03)
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