Heptapeptides synthesis

Scheme 8. AcOZ strategy for the synthesis of palmitoylated and farnesylated N-Ras heptapeptide...

The suitability of the Aloe group for the construction of lipidated peptides is emphasized by the synthesis of the maleimidocaproyl-modified, S-palmi-toylated and farnesylated heptapeptide 16 which corresponds to the N-Ras C-terminus (Scheme 10).1211 In contrast to classical urethane-type protecting groups, the Aloe group can be removed in the presence of additional functional groups and under neutral conditions. It is therefore a very convenient protecting group for the synthesis of very hydro-phobic lipid-modified peptides, which are not soluble in the aqueous media required for enzyme catalyzed transformations. 

Scheme 10. Synthesis of maleimidocaproyl (MIC) modified heptapeptide using the Aloe strategy. TFA trifluoroacetic acid, EDC ...

Hepatotoxins include microcystins, which are cyclic heptapeptides (Fig. 5.1a) and cylindrospermopsin, a sulfated guanidinium alkaloid (Fig. 5. lb). Microcystins bind to certain protein phosphatases responsible for regulating the distribution of cytoskeletal proteins (Zurawell et al. 2005 Leflaive and Ten-Hage 2007). Hepatocytes exposed to microcystins eventually undergo cellular deformation, resulting in intra-hepatic bleeding and, ultimately, death (Carmichael 2001 Batista et al. 2003). In contrast, cylindrospermopsin appears to have a different mode of activity, possibly involving inhibition of protein or nucleotide synthesis (Codd et al. 1999 Froscio et al. 2003 Reisner et al. 2004). Nevertheless, microcystins are the most common cyanotoxins isolated from cyanobacterial blooms (Sivonen and Jones 1999). 

Scheme 15 Synthesis of the doubly palmitoylated heptapeptide corresponding to the C-terminus of hemagglutinin A bearing an N-terminal NBD function using Boc, Aloe, and the allyl ester as protecting groups.

Table 5 Examples for the Synthesis of Cyclic Heptapeptides and Larger Systems 11136309327 329 ...

A. General description Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Eptifibatide binds to the platelet receptor glycoprotein (gp) Ilb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophifized. 

L. patella from Fiji contained patellins 1-5 (50-54) [82] and earlier, solution- and solid-state conformational studies were carried out on patellin 2 (51), and the structure was determined by X-ray analysis [83]. A Lissoclinum sp. from the Great Barrier Reef yielded patellins 3 (52), 5 (54) and 6 (55) and the heptapeptide trunkamide A (56) [82]. Compounds 50-56 were all identified by interpretation of spectral data and through use of Marfey s method to determine the absolute stereochemistry of the constituent amino acids [82]. A total synthesis of the proposed structure of trunkamide A (56) revealed that the structure... 

Cyclodidemnamide (60) is a weakly cytotoxic, heptapeptide from D. molle from the Philippines [90]. Total synthesis of the proposed structure of cyclodidemnamide gave a product with different spectral data to those of the natural product, which is thought to be a stereoisomer [91]. The stereochemistry of one of the two valine residues in cyclodidemnamide was revised from L-valine to D-valine as a result of the total synthesis of both isomers [92] and the configuration was also reassigned as a result of total synthesis [93]. The hexapeptides, comoramides A (61) and B (62), were isolated from D. molle from Mayotte lagoon in the Comoros Islands, while the heptapeptides, mayotamides A (63) and B (64) were isolated from a separate collection of D. molle from the Comoros Islands [94]. 

Not only this heptapeptide but also the entire amino acid sequence of a-melanotropin is found within the sequence of corticotropin (Fig. 30-2), which has an additional 29 amino acids at the C-terminal end.25 The same heptapeptide was also found in the lipotropins. The explanation is, in part, that several of these hormones arise from a single 31-kDa precursor protein called prepro-opiomelanocortin.25 26 It contains an N-terminal signal sequence that is removed shortly after synthesis, as well as pairs of adjacent basic residues (Arg-Arg, Arg-Lys, Lys-Arg and Lys-Lys) at a number of places (Fig. 30-2). After removal of the... 

Another tunicate, Didemnum molle, has been shown to contain a novel series of cyclic peptides. They include the hexapeptides comoramides A (391) and B (392) [301] and the heptapeptides, mollamide (393) [302], cyclodidemnamide (394) [303], and mayotamides A (395) and B (396) [301]. The structures of these compounds were elucidated from spectral data, degradation experiments and, in the case of mollamide (393), by X-ray analysis. The total synthesis of cyclodidemnamide led to the revision of its structure [304]. All of them exhibited cytotoxic activity and 393 also inhibited RNA synthesis [302]. 

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

Polymyxin B, (Section 16.1.6) is a cyclic heptapeptide with a pendent tripeptide segment that has topical antibiotic properties. The solid-phase synthesis is carried out with appropriate side-chain protections. The linear heptapeptide is removed from the resin and cyclized to yield the polymyxin B,. The synthesis of the peptidomimetic (S)-6-methyloctanoic acid is also outlined.136 ... 

Vancomycin (Section 16.1.7) represents a major part of the presentation of Section 16. Vancomycin is a heptapeptide-like structure with interlocking macrocyclic ring systems linked to a disaccharide. Three representative syntheses of vancomycin aglycon are presented. They include a most impressive total synthesis from the Evans Group (Section 16.1.7.1), 37,38 the Nicolaou Group (Section 16.1.7.2), 39 and the Boger Group (Section 16.1.3). 40 Finally, the chapter is concluded with the Nicolaou total synthesis of vancomycin. 41 ... 

Scheme 4 Schematic Description of the Synthesis of the Protected Heptapeptide Boc-L-Lys[Z(2-Cl)]-L-Leu-L-Glu(OBzl)-L-Ala-L-Leu-L-Glu(OBzl)-Gly-OHt21l...

Fig. 5. Solid-phase synthesis of the AmAbz scaffold-containing heptapeptide 19. (i) Piperidine-DMF (l 4) (ii) amino acid building block, BOP/HOBt/DIEA, DMF (iii) Fmoc-Phe, DIC, CH2C12 (iv) TFA, H2Q, TIS (95 2.5 2.5, v/v/v).

Use of AmAbz Building Blocks in the Solid-Phase Synthesis of Peptidomimetics The Typical Example of Heptapeptide 1925... 

Synthesis of a Linear Heptapeptide Library with 19 Eukaryotic Amino Acids (Cysteine Excluded)... 

Thus, the mRNA strand codes for synthesis of the heptapeptide ... 

M Bodanszky, J Martinez, GP Priestly, JD Gardner, V Mutt. Synthesis and properties of a biologically active analog of the C-terminal heptapeptide with e-hydroxy-norleucine sulfate replacing tyrosine sulfate. J Med Chem 21 1030-1037, 1978. 

Various cyclization techniques have been used in the past, which include disulfide bond [61], side-chain lactam [59], and head-to-tail amide bond formation [62], In most cases, the readiness of an open-chain precursor to cyclize depends on the size of the ring and the sequence of the peptide to be cyclized. Usually, ring closure with hexa- and pentapeptides is somewhat hampered however, the cyclization may be enhanced by the presence of turn structure inducing amino acids such as glycine, proline, and D-amino acids, etc., as was the case in the study of McBride et al. [63], Spatola et al. [64] have recently conducted extensive studies in these aspects and several cyclic penta-, hexa-, and heptapeptide libraries were prepared and analyzed. Their results showed that rapid cyclization rates can be achieved with optimized synthesis and cyclization procedures, and many combinations of cyclic peptides can be formed in high quality if they contain structural features that make cyclization more facile. 

Up to this point only amino acids, di- and tripeptides had been considered. However, we wanted to see if the Q-concept could be extended to higher peptides as well. Stepwise we synthesized a heptapeptide and followed the change of the taste. The following Table VIII shows this synthesis... 

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