Cyclic hexapeptide

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.)...

In addition to the development of the powerful chiral additive, this study also demonstrated that the often tedious deconvolution process can be accelerated using HPLC separation. As a result, only 15 libraries had to be synthesized instead of 64 libraries that would be required for the full-scale deconvolution. A somewhat similar approach also involving HPLC fractionations has recently been demonstrated by Griffey for the deconvolution of libraries screened for biological activity [76]. Although demonstrated only for CE, the cyclic hexapeptides might also be useful selectors for the preparation of chiral stationary phases for HPLC. However, this would require the development of non-trivial additional chemistry to appropriately link the peptide to a porous solid support. 

This type of yvn-seleclivc aldol addition has been applied in the synthesis of the unusual L-threonine based amino acid, (2,S, 3/ ,6F)-3-hydroxy-4-methyl-2-methylamino-6-octenoic acid, of cyclosporine104, of the cyclic hexapeptide echinocandin105, and of the antibiotic ionomycin97. 

Pan CP, Callis PR, Barkley MD (2006) Dependence of tryptophan emission wavelength on conformation in cyclic hexapeptides. J Phys Chem B 110(13) 7009-7016... 

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. 

The structurally related myxochromides Aj.j are cyclic hexapeptides produced by several Myxococcus species. These examples contain a proline residue, which is not present in myxochromides Si 3, as the fourth amino acid in their peptide core. The NRPSs responsible for myxochromides A and S biosynthesis have exacdy the same module and domain organization thus, the fourth module of the myxochromide S synthetase must be skipped to account for the natural product. Biochemical experiments revealed that the A domain of this module activates L-proline, but the adjacent PCP domain cannot be phosphopantetheinylated by a PPTase. These results suggest that the C domain of module 5 reacts directly with the tripeptide intermediate bound to the PCP domain of module 3 in myxochromide S biosynthesis. A similar example of domain skipping has been noted in the biosynthesis of the mannopeptimycins. ... 

Structurally unique, potent, and selective oxytocin antagonistic agents characterized by a cyclic hexapeptide structure have recently been isolated from the broth filtrate of a novel Streptomyces silvensis strain [434,435]. As shown in formula (106), these compounds contain two hexahydro-3-pyrid-azinecarboxylic acid moieties. A study has been made of their structural modifications (including oxidation of the reduced pyridazine nuclei) [436]. 

General mineral nutrition status improvement for the host plant has been studied frequently to understand the roles of endophytic fungi. Iron nutrition, however, has been studied only occasionally. P. fortinii strains obtained from Pinus sylvestris, Abies alba, Picea abies, and Carex curvula (the last a monocotyledonous plant) were found to produce the cyclic hexapeptide siderophores ferricrocin (73), ferrirubin (74) and ferrichrome C (75). The concentration and pattern of siderophore production was dependent on ferric ion concentration, pH of the medium, and the strain of endophyte. 

Ferrichrome was the first siderophore to be isolated and characterized from the fungi Ustilago sphaerogena in 1952. It is a cyclic hexapeptide with the sequence cycto[(Gly)3-(Al -acetyl-Af -hydroxy-L-ornithine)3] (1) . The biologically active ferrichromes form iron(ni) complexes with a left-handed A-cis helical twist. 

Design of Novel Cyclic Hexapeptide Somatostatin Analogs from a Model of the Bioactive Conformation... 

FREIDINGER AND VEBER Cyclic Hexapeptide Somatostatin Analogs 171... 

Scheme 2. Synthesis of N -Methyl Lysine Cyclic Hexapeptides...

Cyclic hexapeptides can be considered as the classical and the most prominent representatives among cyclic peptides. Natural products are numerous and widespread (see Scheme 11), e.g. segetalin A,[278] bouvardin/279280 RA-IIlJ281-283 or pneumocandin B0,[284 286] and this type of ring structure has frequently been used to stabilize conformational preferences of bioactive portions of larger peptides or even proteins. 

Scheme 11 Structures of the Naturally Occurring Cyclic Hexapeptides Segetalin A, 2781 Bouvardin, 279-2801 Pneumocandin b, 284-2861 and of a Synthetic Cyclic Somatostatin Analogue 2871...

The conformational properties of cyclic hexapeptides have been extensively investigated over decades by the use of suitable model systems.1137-288 With appropriate peptide sequences the phenomena of cycloenantiomerism and cyclodiastereomerism have been defined 289,290 and reverse turns have been classified for model ring structures. 206 Similarly, the retro-inverso concept was established for the first time with cyclic hexapeptides 130 in this context it is noteworthy that the total retro-inverso structure of a cyclic peptide is especially easy to synthesize, as it does not require specific building blocks but only inverted chirality and full-sequence reversal. 265 ... 

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