Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues

Xuyuan Gu, Jinfa Ying, Byoung Min, James P. Cain, Peg Davis, Patrick Willey, Edita Navratilova, Henry I. Yamamura, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of ω-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]- Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.

Original languageEnglish (US)
Pages (from-to)151-163
Number of pages13
JournalBiopolymers - Peptide Science Section
Volume80
Issue number2-3
DOIs
StatePublished - 2005

Fingerprint

Leucine Enkephalin
Dipeptides
Scaffolds
Thiazolidines
Ligands
Peptidomimetics
Peptides
Biological Assay
Amino Acids
Bioassay
Scaffolds (biology)
Bioactivity
Conformations
Amino acids
Derivatives

Keywords

  • β-turn mimetics
  • Bicyclic dipeptide
  • Leu-enkephalin
  • Solid-phase parallel synthesis
  • Synthetic methodology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues. / Gu, Xuyuan; Ying, Jinfa; Min, Byoung; Cain, James P.; Davis, Peg; Willey, Patrick; Navratilova, Edita; Yamamura, Henry I.; Porreca, Frank; Hruby, Victor J.

In: Biopolymers - Peptide Science Section, Vol. 80, No. 2-3, 2005, p. 151-163.

Research output: Contribution to journalArticle

Gu, Xuyuan ; Ying, Jinfa ; Min, Byoung ; Cain, James P. ; Davis, Peg ; Willey, Patrick ; Navratilova, Edita ; Yamamura, Henry I. ; Porreca, Frank ; Hruby, Victor J. / Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues. In: Biopolymers - Peptide Science Section. 2005 ; Vol. 80, No. 2-3. pp. 151-163.
@article{4bedd1e951b04cf49fe55826cccf00d7,
title = "Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues",
abstract = "Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of ω-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]- Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.",
keywords = "β-turn mimetics, Bicyclic dipeptide, Leu-enkephalin, Solid-phase parallel synthesis, Synthetic methodology",
author = "Xuyuan Gu and Jinfa Ying and Byoung Min and Cain, {James P.} and Peg Davis and Patrick Willey and Edita Navratilova and Yamamura, {Henry I.} and Frank Porreca and Hruby, {Victor J}",
year = "2005",
doi = "10.1002/bip.20208",
language = "English (US)",
volume = "80",
pages = "151--163",
journal = "Biopolymers",
issn = "0006-3525",
publisher = "John Wiley and Sons Inc.",
number = "2-3",

}

TY - JOUR

T1 - Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues

AU - Gu, Xuyuan

AU - Ying, Jinfa

AU - Min, Byoung

AU - Cain, James P.

AU - Davis, Peg

AU - Willey, Patrick

AU - Navratilova, Edita

AU - Yamamura, Henry I.

AU - Porreca, Frank

AU - Hruby, Victor J

PY - 2005

Y1 - 2005

N2 - Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of ω-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]- Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.

AB - Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of ω-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]- Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.

KW - β-turn mimetics

KW - Bicyclic dipeptide

KW - Leu-enkephalin

KW - Solid-phase parallel synthesis

KW - Synthetic methodology

UR - http://www.scopus.com/inward/record.url?scp=20344370233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20344370233&partnerID=8YFLogxK

U2 - 10.1002/bip.20208

DO - 10.1002/bip.20208

M3 - Article

C2 - 15660379

AN - SCOPUS:20344370233

VL - 80

SP - 151

EP - 163

JO - Biopolymers

JF - Biopolymers

SN - 0006-3525

IS - 2-3

ER -