- Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues
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Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schoellkopf chiral auxiliary, this intermediate was obtained in 88% ee. [(S)-Aba3-Gly4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding Repimer was considerably less potent. In contrast, the [(R)-α-MeAba3-Gly4]dermorphin isomer was more potent than its Sepimer. Tar-MD simulations of both non-methylated [Aba3-Gly4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the Nterminus of the peptide, without however, adopting a stabilized β-turn conformation. The α-methylated analogues, on the other hand, exhibited a typeI/I' β-turn conformation over the α-MeAba3 and Gly4 residues, which was stabilized by a hydrogen bond involving Tyr5-HN and D-Ala2-CO.
- Vandormael, Bart,de Wachter, Rien,Martins, Jose C.,Hendrickx, Pieter M.S.,Keresztes, Attila,Ballet, Steven,Mallareddy, Jayapal R.,Toth, Fanni,Toth, Geza,Tourwe, Dirk
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p. 2035 - 2047
(2012/07/03)
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