Linear tetrapeptides

The influence of backbone flexibility was seen, for example, when the stability of the linear tetrapeptide 6.70 was compared to that of a cyclic hexa-peptide derivative of the same sequence [91]. Indeed, the cyclic peptide was approximately one order of magnitude more stable than the linear peptide in the pH range of 2-7. The results at higher pH values were inconclusive since the stability of the cyclic peptide decreased dramatically due to the degradation of a disulfide bond absent in the linear peptide. 

Ramstad proposed a ring closure of a linear tetrapeptide to Agurell s compound 67 which could either epimerize irreversibly to the d-proline compound 18 or undergo oxidative ring closure to the peptide alkaloids as also proposed by Agurell. Any of the observations reported... 

Nakano, Y., Yoshida, W., and Scheuer, P. J., Pupukeamide, a linear tetrapeptide from a cephalaspidean mollusk Philinopsis speciosa, Tetrahedron Lett., 37, 8993, 1996. 

Proline has long been known to help a peptide adopt a reverse-turn conformation (71). For example, the classic type VI turn was defined as having a cm-amide bond between residues i + 1 and i + 2, which proline facilitates in the i + 2 position due to its disubstituted amide nitrogen. The sequence d-Pro-l-Pro in particular has been found to adopt a reverse-turn conformation (84-86) and alternating d/l amino acid sequences facilitate cycli-zation of small peptides as discussed in a review of cyclization of peptides and depsipeptides by Davies (87). Particular difficulties in cyclization of linear tetrapeptides containing residues of the same chirality have been found (88). Durani has discussed designing small folded proteins based on an alphabet of d- and L-amino acids (89). 

Nazumamide A (164), a thrombin inhibitory linear tetrapeptide of marine origin, is effectively constructed using DEPC.64 Stepwise incorporation of each amino acid residue is efficiently carried out by use of DEPC as a coupling agent. 

Further examination of the same sponge that contained the thrombin-inhibitory cyclotheonamides [8], led to the isolation of a thrombin-inhibitory linear tetrapeptide, nazumamide A (58) [53]. It is the first naturally occurring peptide possessing the N-2,5-dihydroxybenzoate terminus. The discovery of thrombin inhibitors is of extreme interest due... 

Richarz R, Wiithrich K (1978) C NMR chemical shifts of common amino acid residues measured in aqueous solutions of linear tetrapeptides H—Gly—Gly—X—L-Ala—OH. Biopolymers 17 2133-2141... 

Figure 28. Boc-LPro-Aib-LAla-Aib-OBzl, a linear tetrapeptide exhibiting an a helix (Smith...

In linear tetrapeptides for the ends to meet, only one of the four peptide bonds needs to have the c/s-configuration. Thus the exclusive presence of imino acids is not essential, cyclic tetrapeptides were found in nature even with exclusively a-amide bonds. R.O. Studer in 1969 synthesized the natural fungisporin, cyclo-(D-Val-L-Val-D-Phe-L-Phe) [28]. When discussing cyclization of pentapeptides, we shall come back to the doubling reaction and to gramicidin S. 

Transport of metal picrate across a chloroform liquid membrane was examined in a U-shaped tube at 25°. The source aqueous phase (pH 7.2) contains a metal chloride and picric acid. The alkali metal cations used were Na". K, and Rb, and the alkaline earth metal cations Mg " ", Ca ", and Ba ". The chloroform phase contains an ion carrier. The second aqueous phase was adjusted to pH 7.2. Linear octapeptides Boc-[Gly-L-Lys(Z)-Sar-L-Pro]2 0H (LGLSP2-0H) and Boc-[Gly-L-Lys(Z)-Sar-L-Pro]2-OCH3 (LGLSP2-0M), cyclic tetrapeptide c-[Gly-L-Lys(Z)-Sar-L-Pro] (CGLSPl), and linear tetrapeptide Boc-Gly-L-Lys(Z)-Sar-L-Pro-OH (LGLSPl-OH) were used as related petidic carriers. In addition, valinomycin and dibenzo-18-crown-6 were employed as a ionophore. The amount of cation transported to the second aqueous phase through membrane was determined spectrophotometrically at 355 nm. 

Nonpowdery polymer easy to filter can be used in a column, used for synthesis of linear tetrapeptides, and peptide substrate for porcine elastase Tetrapeptide synthesis... 

Citronamides A and B are unusual linear tetrapeptides isolated from the Australian spedes Citronia astra collected from Day Reef, North Queensland. These peptides contain two new amino acids, 3-(2-oxo-2,3-dihydro-lH-imidazol-4-yl)serine and 6-amino-7-(4-methoxyphenyl)-heptanoic add and a carbamate-containing a-iduronic add (Carroll, Duffy, and Avery, 2009). 

Hayashi, K., Hamada, Y., and Shioiri, T. (1992) Synthesis of nazumamide A, a thrombin-inhibitory linear tetrapeptide, Irom a marine sponge Theonella sp. Tetrahedron Lett., 33, 5075-5076. 

Rich, D. H., and P. Mathiaparanam Synthesis of the Cyclic Tetrapeptide Tentoxin. Effect of an N-Methyldehydrophenylalanyl Residue on Conformation of Linear Tetrapeptides. Tetrahedron Letters 1974, 4037. 

The potent biological activity of the cyclic tetrapeptides coupled with their unusual structures has sparked extensive synthetic investigation into these compounds to establish SAR and identify analogues with improved biological profiles. Typically, these syntheses are carried out in solution-phase as in Schreiber s approach to trapoxin (Scheme 4.1). An exception is the total synthesis of microsporin A by Silverman using a solid-phase approach (Scheme 4.2). The Kenner safety-catch sulfonamide resin was used to assemble the linear tetrapeptide 17, followed by resin activation towards nucleophilic attack by alleviation of the sulfonamide with iodoacetonitrile. Boc deprotection of the N-terminus then induced macrocyclization to cleave the natural product from the resin. 

Williams DE et al (2011) Padanamides A and B, highly modified linear tetrapeptides produced in culture by a Streptomyces sp. isolated firom a marine sediment. Org Lett 13 3936-3939... 

---