Synthesis of Enantiopure 7-Substituted Azepane-2-carboxylic Acids as Templates for Conformationally Constrained Peptidomimetics (original) (raw)
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Backbone cyclization: A new method for conferring conformational constraint on peptides
Biopolymers, 1991
This article describes a new concept of medium-and long-range cyclization of peptides through "backbone cyclization." In this approach, conformational constraints are conferred on a peptide by linking a-substituted alkylidene chains replacing N " or C" hydrogens in a peptidic backbone. Backbone cyclization, which is divided into N-backbone and C-backbone cyclizations, allow for new modes of cyclization in addition to the classical ones that are limited to cyclization through the side chains and/or the amino or carboxyl terminal groups. The article also describes the application of the N-backbone cyclization to the active region of substance P. Conformational constraints of this peptide by the classical cyclization modes led to inactive analogues whereas N-backbone cyclization provided an active, selective, and metabolically stable analogue.
Peptides, 2011
In earlier work, we synthesized a cyclic 9-amino acid peptide (AFPep, cyclo[EKTOVNOGN]) and showed it to be useful for prevention and therapy of breast cancer. In an effort to explore the structure-function relationships of AFPep, we have designed analogs that bear a short 'tail' (one or two amino acids) attached to the cyclic peptide distal to its pharmacophore. Analogs that bore a tail of either one or two amino acids, either of which had a hydrophilic moiety in the side chain (example: cyclo[EKTOVNOGN]FS) exhibited greatly diminished biological activity (inhibition of estrogen-stimulated uterine growth) relative to AFPep. Analogs that bore a tail of either one or two amino acids which had hydrophobic (aliphatic or aromatic) side chains (example: cyclo[EKTOVNOGN]FI) retained (or had enhanced) growth inhibition activity. Combining in the same biological assay a hydrophilic-tailed analog with either AFPep or a hydrophobic-tailed analog resulted in decreased activity relative to that for AFPep or for the hydrophobic-tailed analog alone, suggesting that hydrophilic-tailed analogs are binding to a biologically active receptor. An analog with a disrupted pharmacophore (cyclo[EKTOVGOGN]) exhibited little or no growth inhibition activity. An analog with a hydrophilic tail and a disrupted pharmacophore (cyclo[EKTOVGOGN]FS) exhibited no growth inhibition activity of its own and did not affect the activity of a hydrophobic-tailed analog, but enhanced the growth inhibition activity of AFPep. These results are discussed in the context of a two-receptor model for binding of AFPep and ringand-tail analogs. We suggest that tails on cyclic peptides may comprise a useful method to enhance diversity of peptide design and specificity of ligand-receptor interactions.
β 2 -Amino Acids in the Design of Conformationally Homogeneous c yclo -Peptide Scaffolds
The Journal of Organic Chemistry, 2006
Herein, we report studies on the influence of chiral 2-amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic R-tetrapeptide cyclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the R-Phe replaced by either an (S)-or an (R)-2 hPhe residue (i.e., cyclo(-(R)-2 hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)-2 hPhe-D-Pro-Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-2 hPhe-) (3a), and cyclo(-Phe-D-Pro-Lys-(R)-2 hPhe-) (3b)), were all synthesized through solidphase procedures followed by solution-phase cyclization. Initially, all five cyclo-peptides were analyzed by 1 H NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X-ray crystallographic study on the side chain-protected (Boc) 2a revealed the solid-state structure of this peptide. The results presented herein, together with previous literature data on 3-amino acid residues, conclusively demonstrate the potential of-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors.
Head-to-Backbone Cyclization of Peptides on Solid Support by Nucleophilic Aromatic Substitution
The Journal of Organic Chemistry, 2002
A new versatile synthetic route is presented for the cyclization of tripeptides on solid support using nucleophilic aromatic substitution in the cyclization step. Identification of all conformers within a limit of 3 kcal/mol from the identified global minimum conformations by Monte Carlo conformational searching reveals that five out of six synthesized compounds have well-defined peptide backbone conformational properties. This was determined by clustering the identified conformers against a filter of seven to nine torsion angles in the peptide backbone. Thus, the results meet our goal to find synthetic routes to peptides that are conformationally sufficiently locked to serve as convenient leads for further development of pharmacophoric models. The strategy is based on Fmoc-peptide chemistry on a N-aminoethyl-substituted glycine bound to the commercially available Rink amide PS-resin. After deprotection of the N-terminus of the tripeptide, it is acylated with a fluoronitrobenzoic acid. Subsequently, a Boc group on the N-bound aminoethyl substituent is selectively deprotected allowing cyclization from the head (N-terminus) to the backbone substituent, thereby leading to the desired cyclized tripeptides. A number of representative examples of peptides cyclized by this method have been synthesized and characterized by NMR. Protecting groups that allow the incorporation of side chain functionalized amino acids have been found. Thus, the route provides access to generic libraries of conformationally restricted peptide sequences expressing a range of proteinogenic pharmacophores.
Backbone Cyclized Peptide Analogs
2017
3.988,304 10/1976 Garsky .................................. 260/78 A 4,011, 182 3/1977 Sarantakis. 4,054,558 10/1977 Garsky ............................. 260/112.5 S 4,187,217 2/1980 Chipens et al. .................. 260/112.5 R 4,191,754 3/1980 Veber et al. ............................ 424/177 4,235,886 11/1980 Freidinger et al. ... 424/177 4,310,518 1/1982 Freidinger et al. ... 424/177 5,364,851 11/1994 Joran ....................................... 530/345 5,371,070 12/1994 Koerber et al. ............................. 514/9
Small and Simple, yet Sturdy: Conformationally Constrained Peptides with Remarkable Properties
International Journal of Molecular Sciences
The sheer size and vast chemical space (i.e., diverse repertoire and spatial distribution of functional groups) underlie peptides’ ability to engage in specific interactions with targets of various structures. However, the inherent flexibility of the peptide chain negatively affects binding affinity and metabolic stability, thereby severely limiting the use of peptides as medicines. Imposing conformational constraints to the peptide chain offers to solve these problems but typically requires laborious structure optimization. Alternatively, libraries of constrained peptides with randomized modules can be screened for specific functions. Here, we present the properties of conformationally constrained peptides and review rigidification chemistries/strategies, as well as synthetic and enzymatic methods of producing macrocyclic peptides. Furthermore, we discuss the in vitro molecular evolution methods for the development of constrained peptides with pre-defined functions. Finally, we bri...
Cyclopentapeptides as Flexible Conformational Templates
Journal of the American Chemical Society, 2000
Studies of 3D models for cyclopentapeptides (CPP's) employing only NMR spectroscopy encounter a serious problem. Because of conformer averaging, 3D structure(s) derived directly from NMR data may not correspond to the energy minimum (minima) with low relative conformational energy. At the same time, independent energy calculations can determine all low-energy conformers for the CPP backbone. The two approaches are compared in this study by results obtained for cyclo(D-Pro 1 -Ala 2 -Ala 3 -Ala 4 -Ala 5 ). Contrary to the conclusion (predominance of the II′γ type conformer) of earlier NMR studies, independent energy calculations found a different family of low-energy 3D structures that are consistent both with the NMR data in DMSO and with the known X-ray data on CPP's. The preferable Ala 4 conformations were found in the R R /R L regions suggesting studies of cyclo(D-Pro 1 -Ala 2 -Ala 3 -Aib 4 -Ala 5 ) which was synthesized. Further NMR studies confirmed the results of the independent energy calculations. The independent energy calculations have been applied also to cyclo(Arg 1 -Gly 2 -Asp 3 -D-Phe 4 -Val 5 ) and cyclo(Arg 1 -Gly 2 -Asp 3 -Phe 4 -D-Val 5 ). Both peptides are almost equally potent inhibitors of binding of R IIb 3 integrins to fibrinogen and of R V 3 integrins to vitronectin. If both of them possess a NMR-predicted conformer of the II′γ type, however, the conformations of the active sequence, Arg 1 -Gly 2 -Asp 3 , should be dissimilar in these two peptides. This discrepancy is eliminated in the 3D pharmacophore model proposed by independent energy calculations. The model is also in good agreement with the model by other authors that was confirmed by X-ray studies. Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. Rothemund, S.; Brudel, M.; Beyermann, M.; Carpino, L. A.; Bienert, M. In Peptides. Chemistry, Structure and Biology; Proceedings of the Thirteenth American Peptide Symposium; Hodges, R. S., Smith, J. A., Eds.; ESCOM: Leiden, 1995; pp 95-96. (7) Ehrlich, A.; Brudel, M.; Beyermann, M.; Winter, R.; Carpino, L. A.; Bienert, M.