Cyclic Pseudopeptides Research Articles

Synthetic Receptors Based on Abiotic Cyclo(pseudo)peptides.

Work on the use of cyclic peptides or pseudopeptides as synthetic receptors started even before the field of supramolecular chemistry was firmly established. Research initially focused on the development of synthetic ionophores and involved the use of macrocycles with a repeating sequence of subunits along the ring to facilitate the correlation between structure, conformation, and binding properties. Later, nonnatural amino acids as building blocks were also considered. With growing research in this area, cyclopeptides and related macrocycles developed into an important and structurally diverse receptor family. This review provides an overview of these developments, starting from the early years. The presented systems are classified according to characteristic structural elements present along the ring. Wherever possible, structural aspects are correlated with binding properties to illustrate how natural or nonnatural amino acids affect binding properties.

Selectivity Modulation and Structure of α/aza-β3 Cyclic Antimicrobial Peptides.

Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β3 -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza-β3 -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β3 residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β3 -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach.

Impact of Cα‐Chirality on Supramolecular Self‐Assembly in Cyclo‐2:1‐[α/aza]‐Hexamers (d/l‐Phe‐azaPhe‐Ala)2

The design of new cyclic pseudopeptides of the sequence 2:1‐[α/aza]‐hexamers, which contain aza‐amino acid motifs, has gained much prominence to be involved in several potential applications. X‐ray, FTIR, and NMR spectroscopy studies showed the ability of this series to adopt β‐turn conformation in solid state, whereas in solution an equilibrium between the monomeric states (stabilized by β‐turns through intramolecular hydrogen bonds), and supramolecular construction (stabilized by intermolecular hydrogen bonds and π‐π stacking) predominates. Furthermore, both homo‐ and heterochiral 2:1‐[α/aza]‐cyclohexamers 3 and 4, respectively, can self‐assemble into organized 3D structures with increases in concentration that favor the supramolecular construction in which the macrocyles are stacking over each other and stabilized by several non‐covalent intermolecular interactions.

Glycosidase- and β-lactamase-like activity of dinuclear copper(II) patellamide complexes

Prochloron, a blue-green algae belonging to ancient prokaryotes, produces, like other cyanobacteria, cyclic pseudo-peptides, which are also found in its obligate symbiont ascidiae (Lissoclinum patellum). Although research has focused for some time on the putative metabolic function of these cyclic peptides, to date it is still not understood. Their role might be connected to the increased concentrations of divalent metal ions, especially CuII, found in ascidiae. Dinuclear copper(II) complexes of cyclic pseudo-peptides revealed a broad hydrolytic capacity, including carboanhydrase and phosphatase activity. This study reports their β-lactamase as well as α- and β-glycosidase activity with kcat=(11.34±0.91)ˑ10−4s−1 for β-lactamase, kcat=(1.55±0.13)ˑ10−4s−1 for α-glycosidase and kcat=(1.22±0.09)ˑ10−4s−1 for β-glycosidase activity.

Cyclic peptide marine metabolites and CuII

Cyclic pseudo-peptides derived from marine metabolites of the genus Lissoclinum bistratum and Lissoclinum patella have attracted scientific interest in the last two decades. Their structural properties and solution dynamics have been analyzed in detail, elaborate synthetic procedures for the natural products and synthetic derivatives developed, the biosynthetic pathways studied and it now is possible to produce them biosynthetically. Initially, these macrocyclic ligands were studied due to their medicinal and pharmaceutical potential - some of the isolated cyclic pseudo-peptides show high cytotoxic and antiviral activity. A major focus in the last decade has been on their Cu(II) coordination chemistry, as a number of studies have indicated that dinuclear Cu(II) complexes of cyclic peptides may be involved in the ascidians' metabolism, and this is the focus of the present review.

De Novo Cyclic Pseudopeptides Containing Aza-β3-amino Acids Exhibiting Antimicrobial Activities

De novo cyclic pseudopeptides composed of α-amino and aza-β(3)-amino acids were designed with the aim to obtain potential new antimicrobial agents. Antimicrobial cyclic pseudopeptides (ACPPs) are based on the properties of antimicrobial peptides (AMPs), so they are cationic and amphiphilic. Aza-β(3)-amino acids enhance the in vivo half-life of these compounds and offer the possibility to incorporate a large variety of side chains. Most of the 13 ACPPs exert antimicrobial activities in rich media with broad spectrum of antibacterial activities. Selectivity for bacterial over mammalian cells was determined by testing the hemolytic activities of ACPPs against sheep red blood cells (sRBC). We examined the ratio of cationic to hydrophobic residues as well as the type of hydrophobic side chains essential for biological activity of this class of ACPPs. These results will be useful for designing potential candidates for a therapeutic application.

ChemInform Abstract: Synthetic Peptide‐Based Receptors

AbstractReview: 68 refs.

Phosphatase reactivity of a dicopper(ii) complex of a patellamide derivative – possible biological functions of cyclic pseudopeptides

A possible biological function of cyclic pseudo-octapeptides is presented. The dinuclear copper(II) complex of a synthetic analogue ([Cu(2)(H(2)Pat(1))(μ-OH)(OH(2))(2)]) of the naturally occurring ascidiacyclamide is known to have a hydroxo-bridged dicopper(II) site which is able to catalytically transform CO(2) into CO(3)(2-). This complex is shown here to function as a phosphatase mimic, suggesting that the so far unknown biological function of these macrocycles within the ascidians may involve phosphoester hydrolysis.

Cis-Apa: A Practical Linker for the Microwave-Assisted Preparation of Cyclic Pseudopeptides via RCM Cyclative Cleavage

A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.

The Design and Synthesis of Dansyl‐Containing Cyclic Pseudopeptides

AbstractSix cyclic pseudopeptides with the general formula cyclo‐(L‐AA‐D‐Oxd)n [where AA is an α‐amino acid, D‐Oxd is trans‐(4R,5S)‐4‐carboxy‐5‐methyloxazolidin‐2‐one and n = 3, 4] have been designed and efficiently synthesized in the liquid phase in good overall yields. The crucial step is the macrocyclization, which always occurs in satisfactory yields regardless of the cycle dimension and the nature of various functional groups in the side‐chain. Moreover, a dansyl (dansyl = 5‐dimethylamino‐1‐naphthylsulfonyl) unit was introduced into the side‐chain with the aim of preparing a labelled cyclopeptide that can be easily located in a biological environment. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Transition metal complexes of a cyclic pseudo hexapeptide: synthesis, complex formation and catalytic activities

To contribute to a better understanding of metalloenzymes, we studied ion selectivity, complex formation tendencies and catalytic activities of linear and cyclic pseudopeptides. In this contribution, a linear and cyclic pseudo hexapeptide is described. The complex with transition metal ions and the sequence were designed using the programme COSMOS. Different routes of solid-phase synthesis were performed and compared using anchoring by C-terminus or a His side chain, using preformed pseudodipeptide building units or formation of N-functionalized peptide bond during stepwise assembly. The different strategies were compared regarding cyclization tendency, yield and purity. Side-chain anchoring to solid support favours the cyclization but leads to the formation of difficult to separate dioxopiperazine. Both routes require preformed building units. Complex-formation tendencies and selectivity for certain bivalent transition metal ions were experimentally estimated and compared to ones predicted theoretically. CD measurements indicate conformational changes by complex formation with different metal ions. Catalytic activities on oxidation of catechol and hydrolysis of bis-phosphate esters by some metal complexes of linear and cyclic peptide show only low catalytic activities compared to other model peptides and related metalloenzymes. The preference of the cyclic peptide for complexation of Ni(2+) corresponds well to the predictions of COSMOS-NMR force field calculations.

Synthesis, SAR and in vitro evaluation of new cyclic Arg-Gly-Asp pseudopentapeptides containing a s- cis peptide bond as integrin α vβ 3 and α vβ 5 ligands

The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1 H-pyrrolizine-7a(5 H)-carboxylic acid (GPTM) is described. Competition binding assays to purified α vβ 3 and α vβ 5 integrins with respect to [ 125I]echistatin showed a high inhibitory activity for the (2 S,7a S)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2 R,7a R)-GPTM and (2 S,7a S)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp- d-Phe-[ N-Me]Val) in complex with the extracellular fragment of the α vβ 3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand–protein complex.

New Cyclic Arg-Gly-Asp Pseudopentapeptide Containing the β-Turn Mimetic GPTM

The solid-phase synthesis of cyclic pseudopeptides con- taining the Arg-Gly-Asp recognition sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxy- lic acid (GPTM) was accomplished. N-Fmoc-Asp-OAll was an- chored to Wang resin through its side chain and sequentially coupled with N-Fmoc-Gly-OH, N-Fmoc-Arg(Pbf)-OH and N- Fmoc-GPTM-OH. The supported linear pentapeptide smoothly un- derwent head-to-tail cyclization by activation with TBTU/DIPEA. Finally, TFA treatment released the completely deprotected cyclic pseudopentapeptide. Competition binding assays to purified aVb3 and aVb5 integrins showed a high inhibitory activity of cyclo(Arg- Gly-Asp-(2S,7aS)-GPTM).

Insertion of an Aspartic Acid Moiety into Cyclic Pseudopeptides: Synthesis and Biological Characterization of Potent Antagonists for the Human Tachykinin NK-2 Receptor

A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED(50) = 0.27 nmol/kg and 0.15 nmol/kg, respectively).

Synthesis and molecular recognition of novel cyclic pseudopeptides containing L‐glutamic acid or L‐aspartic acid backbones

AbstractNovel cyclic pseudopeptides containing L‐glutamic acid or L‐aspartic acid backbone structures were efficiently synthesized and characterized. Their chiral recognition properties for L‐ and D‐amino acid methyl ester hydrochloride were discussed also.

Estimation of pseudopeptide metal ion complexation tendencies by special MS methods, HPCE and circular dichroism

To obtain more insight into catalytic mechanisms of metallo enzymes and specific metal complexation by proteins we use linear and cyclic pseudopeptides as mimetics. Knowledge about tendencies of complex formation of different ligands with selected transition metal ions is an indispensable prerequisite for the development of homo-and hetero-dinuclear metallo enzyme mimetics. Three pseudotripeptide ligands were investigated with respect to formation tendency and properties of complexes with the transition metal ions Cu2+, Zn2+ Ni2+, Co2+ and Mn2+. To study complexation tendencies we applied different methods. One of the important prerequisites for the application in a secreening of series of peptide ligands is the necessity for a minimal amount of substance. We used and compared certain masspectrometric methods for the estimation of a rank order of complexation of certain transition metal ions. We also applied spectrophotometric titration, circular dichroism measurements, capillary electrophoresis and pH-rate profile of catalytic activity in the attempt to evaluate complex formation tendencies. Except for the spectrophotometric pH-titration and the pH-profile of catalytic activity all methods, were applicable, but each method has its advantages and disadvantages depending on the separation effect of the ligand from the metal complex, and depending on the spectroscopic properties of ligand and complex. The results regarding complex formation are compared to each other. Comparison of pairs by MALDI-TOF-and ESI-MS allows an estimation of the rank order of complexation tendency of one ligand with different metal ions and requires the least amount of substance. The other investigated methods provided additional information on structural properties of the formed complexes; however either they required too much pseudopeptide ligand or were not applicable for all transition metal ions used in this study.

Insertion of 2-Carboxysuccinate and Tricarballylic Acid Fragments into Cyclic-Pseudopeptides: New Antagonists for the Human Tachykinin NK-2 Receptor

A series of cyclic pseudopeptides were synthesized containing the sequence -Trp-Phe-( d)-PheΨCH 2NH-, the terminal ends of which were bound to 2-carboxy succinate or enantiomerically enriched tricarballylic acid to give the final cyclic structures. These two molecules and their subsequent derivatives were screened for h-NK2 receptor binding and functional antagonist activity on the rabbit urinary bladder.

Potent Integrin Antagonists from a Small Library of RGD-Including Cyclic Pseudopeptides

[structure: see text]. A small library of cyclic RGD pseudopentapeptides incorporating stereoisomeric 6,5- and 7,5-fused bicyclic lactams was synthesized with the aim of developing active and selective integrin antagonists. The solid-phase synthesis and activity of these RGD derivatives is described. The approach led to two of the most active known inhibitors of alpha(V)beta3 receptor.

ChemInform Abstract: Synthesis of a New Series of Cyclic Pseudopeptides Containing Pyridine as Backbone Modifier.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis Of A New Series Of Cyclic Pseudopeptides Containing Pyridine As Backbone Modifier

A new class of cyclic pseudo-peptides which contains pyridine and cystine in the backbone structure was synthesized by a simple three-step preparation. The structures of products were characterized by spectroscopic and conventional analytical methods.