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Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues

Bart Vandormael, Rien De Wachter, José Martins UGent, Pieter Hendrickx UGent, Attila Keresztes, Steven Ballet, Jayapal R Mallareddy, Fanni Tóth, Geza Tóth and Dirk Tourwé (2011) CHEMMEDCHEM. 6(11). p.2035-2047
abstract
Dermorphin analogues, containing a (S)- and (R)-4-amino1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the alpha-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-alpha-Me-o-cyanophenylalanine precursor for (S)-alpha-MeAba in acceptable enantiomeric purity. However, by using a Schollkopf chiral auxiliary, this intermediate was obtained in 88% ee. [(S)-Aba 3-Gly 4] dermorphin retained mu-opioid affinity but displayed an increased delta-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-alpha-MeAba3-Gly4] dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4] dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized beta-turn conformation. The alpha-methylated analogues, on the other hand, exhibited a type I/I' beta-turn conformation over the alpha-MeAba3 and Gly4 residues, which was stabilized by a hydrogen bond involving Tyr5-H(N) and D-Ala 2-CO.
Please use this url to cite or link to this publication:
author
organization
alternative title
Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and alpha-MeAba-containing dermorphin analogues
year
type
journalArticle (original)
publication status
published
subject
keyword
beta-turn stabilization, molecular dynamics, ligand design, ligand effects, opioid peptides, PHASE-TRANSFER CATALYSIS, HIGHLY ENANTIOSELECTIVE SYNTHESIS, NUCLEAR-MAGNETIC-RESONANCE, LFA-1 ANTAGONIST BIRT-377, DELTA-OPIOID RECEPTOR, AMINO-ACIDS, RAT-BRAIN, DELTORPHIN-I, STEREOSELECTIVE SYNTHESIS, DISTANCE RESTRAINTS
journal title
CHEMMEDCHEM
ChemMedChem
volume
6
issue
11
pages
2035 - 2047
Web of Science type
Article
Web of Science id
000297416900014
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.151 (2011)
JCR rank
69/259 (2011)
JCR quartile
2 (2011)
ISSN
1860-7179
DOI
10.1002/cmdc.201100314
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2129204
handle
http://hdl.handle.net/1854/LU-2129204
date created
2012-06-01 15:03:40
date last changed
2012-07-05 09:41:29
@article{2129204,
  abstract     = {Dermorphin analogues, containing a (S)- and (R)-4-amino1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the alpha-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-alpha-Me-o-cyanophenylalanine precursor for (S)-alpha-MeAba in acceptable enantiomeric purity. However, by using a Schollkopf chiral auxiliary, this intermediate was obtained in 88\% ee. [(S)-Aba 3-Gly 4] dermorphin retained mu-opioid affinity but displayed an increased delta-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-alpha-MeAba3-Gly4] dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4] dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized beta-turn conformation. The alpha-methylated analogues, on the other hand, exhibited a type I/I' beta-turn conformation over the alpha-MeAba3 and Gly4 residues, which was stabilized by a hydrogen bond involving Tyr5-H(N) and D-Ala 2-CO.},
  author       = {Vandormael, Bart and De Wachter, Rien and Martins, Jos{\'e} and Hendrickx, Pieter and Keresztes, Attila and Ballet, Steven and Mallareddy, Jayapal R and T{\'o}th, Fanni and T{\'o}th, Geza and Tourw{\'e}, Dirk},
  issn         = {1860-7179},
  journal      = {CHEMMEDCHEM},
  keyword      = {beta-turn stabilization,molecular dynamics,ligand design,ligand effects,opioid peptides,PHASE-TRANSFER CATALYSIS,HIGHLY ENANTIOSELECTIVE SYNTHESIS,NUCLEAR-MAGNETIC-RESONANCE,LFA-1 ANTAGONIST BIRT-377,DELTA-OPIOID RECEPTOR,AMINO-ACIDS,RAT-BRAIN,DELTORPHIN-I,STEREOSELECTIVE SYNTHESIS,DISTANCE RESTRAINTS},
  language     = {eng},
  number       = {11},
  pages        = {2035--2047},
  title        = {Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and \ensuremath{\alpha}-MeAba-containing dermorphin analogues},
  url          = {http://dx.doi.org/10.1002/cmdc.201100314},
  volume       = {6},
  year         = {2011},
}

Chicago
Vandormael, Bart, Rien De Wachter, José Martins, Pieter Hendrickx, Attila Keresztes, Steven Ballet, Jayapal R Mallareddy, Fanni Tóth, Geza Tóth, and Dirk Tourwé. 2011. “Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba- and α-MeAba-containing Dermorphin Analogues.” Chemmedchem 6 (11): 2035–2047.
APA
Vandormael, B., De Wachter, R., Martins, J., Hendrickx, P., Keresztes, A., Ballet, S., Mallareddy, J. R., et al. (2011). Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues. CHEMMEDCHEM, 6(11), 2035–2047.
Vancouver
1.
Vandormael B, De Wachter R, Martins J, Hendrickx P, Keresztes A, Ballet S, et al. Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues. CHEMMEDCHEM. 2011;6(11):2035–47.
MLA
Vandormael, Bart, Rien De Wachter, José Martins, et al. “Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba- and α-MeAba-containing Dermorphin Analogues.” CHEMMEDCHEM 6.11 (2011): 2035–2047. Print.