Cyclic pentapeptide

From a structural point of view the OPLS results for liquids have also shown to be in accord with available experimental data, including vibrational spectroscopy and diffraction data on, for Instance, formamide, dimethylformamide, methanol, ethanol, 1-propanol, 2-methyl-2-propanol, methane, ethane and neopentane. The hydrogen bonding in alcohols, thiols and amides is well represented by the OPLS potential functions. The average root-mean-square deviation from the X-ray structures of the crystals for four cyclic hexapeptides and a cyclic pentapeptide optimized with the OPLS/AMBER model, was only 0.17 A for the atomic positions and 3% for the unit cell volumes. 

Anthoine-Dietrich S, Banfi L, Basso A, Damonte G, Guanti G, Riva R (2005) Application of tandem Ugi multi-component reaction/ring closing metathesis to the synthesis of a confor-mationally restricted cyclic pentapeptide. Org Biomol Chem 3(1) 97-106... 

M. Aumailley, M. Gurrath, G. Muller, J. Calvete, R. TimpI, H. Kessler, Arg-Gly-Asp constrained within cyclic pentapeptides, strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment PI, FEBS. Lett. 291(1) (1991) 50-54. 

Scheme 9 Structures of the Cyclic Pentapeptides Astin A-C 2501 and Viscumamide173 254 ...

Scheme 10 Two Frequently Observed Turn Topologies in Cyclic Pentapeptides...

Since there is only a small energy difference between the different conformational states depending upon the presence or absence of a Pro, Gly or N-alkylated amino acid residue, and upon the chirality of the constituent amino acid residues and also to a lesser extent upon the side-chain functionalities, it is not possible to unambiguously predict the conformation of a cyclic pentapeptide. These molecules have often been studied in different solvents and solvent effects were neglected, and/or the methodology to handle such conformational equilibrium was not available. It is only recently that modem NMR techniques and computational procedures have become available to treat this complex problem of fast exchanging conformational equilibria. 36,269,270 ... 

A typical method for the large-scale synthesis of a cyclic pentapeptide is reported in Section 6.8.2.I.I. 

Scheme 26 Stereoisomeric Cyclic Pentapeptide Sublibraries Having the Sequence A-B-C-D-E Based on Scaffold (l)a...

Figure 3 TOCSY Spectra (600 MHz, 300K, DMSO-d6) of the Cyclic Pentapeptide Sequence c[-Asn-Glu-D-His-Ala-Gly-]...

The antineoplastic, cyclic peptide dolastatin 3 (197) was isolated from the sea hare Dolabella auricularia in small quantities [187]. It bears much structural resemblance to the cyclic peptides of tunicates. Synthetic attempts indicated that the original published structure was incorrect [188]. Three reports of research directed towards synthesis of possible components of dolastatin 3 (197) failed to help with the correct structure [189-191]. Reisolation of 197 allowed the determination of the correct sequence of amino acids in this cyclic pentapeptide and the new structure was confirmed by synthesis [192]. Synthesis of dolastatin 3 (197) and the corresponding 12R diastereoisomer permitted study of the solution... 

The RGD sequence was thus constrained into a variety of sheet or /3-turn structures, which were unequivocally determined for each peptide. The biological activity of 18 cyclic peptides was then compared with that of a linear standard, GRGDS, in inhibition assays of tumour cell adhesion. An increase in activity of up to 100-fold was observed for just two cyclic pentapeptides, all others showing a decrease in activity. This identified the required conformation of the RGD backbone. 

Quite recently, we have described the seven-membered ring y-turn mimetic 25f45l (Scheme 16) designed to mimic a proposed bioactive conformation in the cyclic pentapeptide mal-formin family. The synthesis is depicted in Scheme 17. The compounds were tested in a relevant bioassay, but were devoid of activity. 

As with the synthesis of cyclic peptides, various methods have been employed to effect head-to-tail cyclization of these peptides. The most straightforward method remains N-to-C-terminus amide bond formation in solution of the appropriately side-chain-protected peptide in the presence of carboxyl activating agents under basic conditions. 23 However, cyclodimerization reactions have also been employed to produce cyclic decameric peptides whereby two appropriately protected linear pentameric peptides are dimerized and cyclized in the presence of carboxyl activating agents under basic conditions in the same reaction. 23,24 The use of the cyclodimerization reactions, however, has limitations in that it can only be applied to produce symmetrical peptides, and that formation of the cyclic pentapeptide presents a side reaction and thus results in decreased yields of the desired product. 

Morita H, Nagashima S, Takeya K, Itokawa H (1994) A Novel Cyclic Pentapeptide with a (3-Hydroxy-y-chloroproline from Aster tataricus. Chem Lett 2009... 

Structure-activity relationship studies on this cyclic pentapeptide showed that the exchange of the valine by a lysine residue (Lys, K) (compound 36) did not significantly influence activity and selectivity [52]. Because the -amino moiety of the lysine residue can easily be modified, numerous applications of c[RGDfK] have been studied for tumor targeting and imaging [53]. 

Figure 1.12 Structures of cyclic pentapeptides as potent antagonists of the Ofylh integrin.

Coherent transport of vibrational energy is further limited by vibrational energy relaxation. Experiments on the amide I band of different peptides (NMA, apamin, scyllatoxin BPTI, and the cyclic pentapeptide) revealed a vibrational relaxation rate of approximately Ti = 1.2 ps, which is essentially independent of the particular peptide (30,53). A similar value has recently been reported for myoglobin at room temperature, with only a weak dependence of the relaxation rate on temperature down to cryogenic temperatures (140). In other words, vibrational relaxation of the amide I mode reflects an intrinsic property of the peptide group itself rather than a specific characteristic of the primary or secondary structural motifs of the... 

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