Conformation-directed design of cyclic somatostatins containing a ?VI-turn mimetic

Tourwé, Dirk

doi:10.1007/bf00119148

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…Brecx et al . (43) and Tourwe (44) demonstrated, that o ‐aminomethylphenylacetic acid ( o ‐AMPA) is a suitable mimetic for a cis peptide bond. Both α‐ or δ‐benzyl‐substituted o ‐AMPA were good mimics for the Phe 11 ‐Pro 6 bridging unit in L‐363,301 analogs.…”

Section: Somatostatin Analogs Based On Cyclic Hexapeptide L‐363301mentioning

confidence: 99%

Somatostatin analogs

Janecka

Zubrzycka

Janecki

2001

The Journal of Peptide Research

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Somatostatin is a hypothalamic peptide hormone that inhibits the secretion of growth hormone, glucagon, insulin, gastrin and secretin, and also plays a role in neural transmission. Because of its wide range of possible clinical applications hundreds of somatostatin analogs have been synthesized and bioassayed to date. This review gives a historical perspective, summarizing approximately 30 years of research on somatostatin. The main focus is on the structure-activity relationships and conformational studies of the last generation of somatostatin agonists and their selectivity for five somatostatin receptor subtypes. Achievements in the synthesis of nonpeptide somatostatin analogs, as well as the first somatostatin antagonists, are also discussed. Finally, the use of a cyclic somatostatin scaffold to design ligands for other G-protein-coupled receptors, such as opioid and melanocortin receptors, is mentioned.

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Section: Somatostatin Analogs Based On Cyclic Hexapeptide L‐363301mentioning

confidence: 99%

Somatostatin analogs

Janecka

Zubrzycka

Janecki

2001

The Journal of Peptide Research

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“…The absolute configuration of the a-carbon in the N-Me-o~-Bn-o-AMPA-somatostatin analogue has been determined by asymmetric synthesis [7]. Based on the structural similarity between the o~-Bn-o-AMPA-somatostatin and N-Me-a-Bn-o-AMPA-somatostatin analogues, it is assumed that the elution order on RP-HPLC is the same and that the first eluting isomer has the S-configuration and the second eluting compound the Rconfiguration.…”

Section: Configuration Assignment Of the Asymmetric Center Of The Brimentioning

confidence: 99%

Somatostatin analogues containing o-aminomethylphenylacetic acid as a bridge unit

Brecx¹,

Misicka²,

Verheyden³

et al. 1995

Lett Pept Sci

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A new cis-peptide bond mimetic, c~-benzyl-o-aminomethylphenylacetic acid, was synthesized and incorporated in a homodetic somatostatin analogue. Biological binding tests and 2D NMR conformational analysis indicate that the configuration of the bridge-unit asymmetric center and the orientation of the benzyl side chain play a key role in the biological activity of this type of somatostatin analogues.

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Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatic_i+1–prolyl_i+2 amide bond: Implications for type VI β‐turn formation

et al. 2005

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Cis-trans isomerization of amide bonds plays critical roles in protein molecular recognition, protein folding, protein misfolding, and disease. Aromatic-proline sequences are particularly prone to exhibit cis amide bonds. The roles of residues adjacent to a tyrosine-proline residue pair on cis-trans isomerism were examined. A short series of peptides XYPZ was synthesized and cis-trans isomerism was analyzed. Based on these initial studies, a series of peptides XYPN, X = all 20 canonical amino acids, was synthesized and analyzed by NMR for i residue effects on cis-trans isomerization. The following effects were observed: (a) aromatic residues immediately preceding Tyr-Pro disfavor cis amide bonds, with K(trans/cis)= 5.7-8.0, W > Y > F; (b) proline residues preceding Tyr-Pro lead to multiple species, exhibiting cis-trans isomerization of either or both X-Pro amide bonds; and (c) other residues exhibit similar values of K(trans/cis) (= 2.9-4.2), with Thr and protonated His exhibiting the highest fraction cis. beta-Branched and short polar residues were somewhat more favorable in stabilizing the cis conformation. Phosphorylation of serine at the i position modestly increases the stability of the cis conformer. In addition, the effect of the i+3 residue was examined in a limited series of peptides TYPZ. NMR data indicated that aromatic residues, Pro, Asn, Ala, and Val at the i+3 residue all favor cis amide bonds, with aromatic residues and Asn favoring more compact phi at Tyr(cis) and Ala and Pro favoring more extended phi at Tyr(cis). D-Alanine at the i+3 position particularly disfavors cis amide bonds.

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Conformation-directed design of cyclic somatostatins containing a ?VI-turn mimetic

Abstract: The design process and the synthetic problems for the construction of conformationally constrained cyclic somatostatins are described. Highly potent analogs containing o-aminomethylphenylacetic acid or o-aminomethylphenylalanine are obtained.

Cited by 4 publications

References 19 publications

Somatostatin analogs

Somatostatin analogs

Somatostatin analogues containing o-aminomethylphenylacetic acid as a bridge unit

Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatic_i+1–prolyl_i+2 amide bond: Implications for type VI β‐turn formation

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Conformation-directed design of cyclic somatostatins containing a ?VI-turn mimetic

Abstract: The design process and the synthetic problems for the construction of conformationally constrained cyclic somatostatins are described. Highly potent analogs containing o-aminomethylphenylacetic acid or o-aminomethylphenylalanine are obtained.

Cited by 4 publications

References 19 publications

Somatostatin analogs

Somatostatin analogs

Somatostatin analogues containing o-aminomethylphenylacetic acid as a bridge unit

Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatici+1–prolyli+2 amide bond: Implications for type VI β‐turn formation

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Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatic_i+1–prolyl_i+2 amide bond: Implications for type VI β‐turn formation