Cyclopeptides

The cyclopeptide described above was tailored to form stable potassium complexes. It is one of the very few examples of complex peptide syntheses which do not lead to a natural compound. 

The main supramolecular self-assembled species involved in analytical chemistry are micelles (direct and reversed), microemulsions (oil/water and water/oil), liposomes, and vesicles, Langmuir-Blodgett films composed of diphilic surfactant molecules or ions. They can form in aqueous, nonaqueous liquid media and on the surface. The other species involved in supramolecular analytical chemistry are molecules-receptors such as calixarenes, cyclodextrins, cyclophanes, cyclopeptides, crown ethers etc. Furthermore, new supramolecular host-guest systems arise due to analytical reaction or process. 

Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

Fig. 3-3. Comparison of the values of enantiomeric resolution of different DNP-D,L-amino acids at different deconvolution stages of a cyclic hexapeptide sublibrary. Resolution values in a cyclo(Arg-Lys-X-X-X-P-Ala) sublibrary, in the first line, are compared to those obtained in sublibraries with a progressively increasing number of defined positions. All the sublibraries were 30 mM in the running buffer while the completely defined cyclo(Arg-Lys-Tyr-P-Tyr-P-Ala) peptide is used at 10 mM concentration. Conditions cyclopeptide sublibrary in 20 mM sodium phosphate buffer, pH 7.0 capillary, 50 pm i.d., 65 cm total length, 57 cm to the window V = -20 kV, I = 40 electrokinetic injection, -10 kV, 3 s detection at 340 nm. (Reprinted with permission from ref. [75]. Copyright 1998, American Chemical Society.)...

FIGURE 11.7 Structure of cyclopeptides c(Gly -Pi-oAba-5-CH2X) (9) and c(Gly -Pi-mAba-5-CH2X) (10). 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

As for the above cyclopeptides 10, the first step in inactivation process is a selective ring opening. Formation of the acyl-enzyme is then followed by a fast 1,6-elimination and the unmasking of a reactive tethered QIM (Scheme 11.4). 

SCHEME 11.4 Postulated mechanism for inactivation of DPP IV by a functionalized cyclopeptide 11.32... 

Wakselman, M. Xie, J. Mazaleyrat, J.-P. Boggetto, N. Vilain, A. C. Montagne, J.-J. Reboud-Ravaux, M. New mechanism-based inactivators of trypsin-like proteinases. Selective inactivation of urokinase by functionalized cyclopeptides incorporating a sulfoniomethyl-substituted mera-aminobenzoic acid residue. J. Med. Chem. 1993, 36, 1539-1547. 

Nguyen, C. Blanco, J. Mazaleyrat, J.-P. Krust, B. Callebaut, C. Jacotot, E. Hovanessian, A. G. Wakselman, M. Specific and irreversible cyclopeptide inhibitor of dipeptidyl peptidase IV activity of the T-cell activation antigen CD26. J. Med. Chem. 1998, 41, 2100-2110. 

Reboud-Ravaux, M. Convert, O. Mazaleyrat, J.-P. Wakselman, M. Structural factors in the enzymic hydrolysis of cyclopeptides containing an ortho- or meta-amino benzoic acid residue. Bull. Soc. Chim. Fr. 1988, 267-271. 

Boturyn D, Coll J-L, Garanger E et al (2004) Template assembled cyclopeptides as multimeric system for integrin targeting and endocytosis. J Am Chem Soc 126 5730-5739... 

The natural product westiellamide (158) and other unnatural cyclopeptide alkaloids were synthesised by cyclooligomerisation reactions <00T9143>. The benzene-based tripodal tris(oxazolines) 159 were developed as new selective receptors toward alkylammonium ions <00CEJ3399>. 

The pyrrolidine ring is part of numerous natural products, and we have restricted the field to those alkaloids that contain an isolated pyrrolidine ring. We have thus excluded the so-called Sceletium (mesembrine) and Dendrobium (den-drobine) alkaloids, which have also been reviewed (3-5). The pyrrolidine ring is frequently encountered in proline residues of cyclopeptide alkaloids these have been reviewed already (7) and will not be discussed here. 

OH >j C02H H (both diastereomers) Bacteria -Streptomyces sp. (trans isomer is also found in Delonix regia and many collagens) Telomycin - cyclopeptide antibiotic 214, 242... 

Polyoxypeptin - cyclopeptide 250-252 with apoptosis-inducing activity... 

Azumamide E is a cyclotetrapeptide natural product isolated from marine sponge Mycale izuensis. Like most cyclopeptide HDAC inhibitors, these compounds contain D-a-amino acids (D-Phe, D-Tyr, D-Ala, D-Val) which relieve ring strain (Fig. 7). However, they are unique from other natural cyclopeptide HDAC inhibitors with a retroenantio arrangement. 

Apicidin (Fig. 10) was first isolated from fimgus Fusarium pallidoroseum ATCC 74289, MF6040, from Acacia sp. (collected from Santa Rosa National Park Costa Rica) as an antiprotozoal agent. It was found that apicidin was active against wide range of protozoans specially Apicomplexan parasites. The underlying mechanism for this cidal activity was found out to be HDAC inhibition of protozoas. It was also observed that they were very potent HDAC inhibitors when compared to similar cyclopeptide inhibitors known at that time (Table 5). 

Cyclic tautomers of tryptamines and tryptophans, chemistry and reactions, 34, I (1988) Cyclopeptide alkaloids, 15, 165 (1975)... 

Complete structural analysis requires mass spectral and NMR data as well as chemical degradation and analysis of the chirality of the constituent amino acids, determination of the mode of linkage of lysine (a- or s-), the size of the cyclopeptide or cyclodepsipeptide ring, etc. (37). In some cases sttuctures have been proposed based only on mass spectral data. Difficulties arising in this approach were discussed (44). To determine the three-dimensional structure an X-ray... 

Amann C, Taraz K, Budzikiewicz H, Meyer JM (2000) The Siderophores of Pseudomonas fluorescens 18.1 and the Importance of Cyclopeptidic Substructures for the Recognition at the Cell Surface. Z Naturforsch 55c 671... 

Zhu and co-workers used S Ar reactions to create the biaryl ether bond in their synthesis of cyclopeptide alkaloids [55-57] (Scheme 5). The electrophile in this case is an aryl fluoride, often additionally activated by an electron-withdrawing group such as a nitro group. The necessity of such an activation auxiliary obviously has a negative impact on general applicability of this method. 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

A multicomponent reaction/cyclization strategy was employed to synthesize simplified cyclopeptide alkaloid analogues 82. The enamide double bond found in many natural derivatives is missing, but biologically active cyclopeptide alkaloids with a hydrated enamide double bond (like sanjoi-nine G1 [55, 56]) are known. The synthesis is considerably simplified by omitting this unsaturation, obviously not required for biological activity. 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

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