Ni-to-Ni+ 3-ethylene-bridged partially modified retro-inverso tetrapeptide beta-turn mimetic: design, synthesis, and structural characterization.
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 beta-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 beta-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 N(i)-to-N(i+3)-ethylene-bridged linear precursor: Further elaboration of the linear precursor generated the ethylene-bridged model compounds (16) and (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' beta-turn. Transformation of CONH(2) in the N-terminal amino acid residue of 16 into NHCOCH3 in 18 resulted in the formation of a hydrogen bond between the NH of gPhe-COCH3 and the C-terminal carboxyl of Gly, initiating an antiparallel beta-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.
Department of Medicine, Bone and Mineral Metabolism Unit, Charles A. Dana and Thorndike Laboratories, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, Massachusetts 02215, USA.
Yinglin
Y
Han
Craig
C
Giragossian
Dale F
DF
Mierke
Michael
M
Chorev
D000478:Alkylation; D002384:Catalysis; D002853:Chromatography, Liquid; D005030:Ethylenes / Q000737:chemistry*; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D011487:Protein Conformation
D005030:Ethylenes; D006572:Heterocyclic Compounds, Bridged-Ring; D009842:Oligopeptides; D010456:Peptides, Cyclic