Tetrapeptides, cyclic, conformations

Contrary to the cyclic tripeptides, cyclic tetrapeptides are found as natural products such as chlamydocin,1208-2111 HC-toxin,1212-2131 WF 3161,1214,2151 or tentoxin,173,216-2191 which all exhibit interesting pharmacological properties, e.g. phytotoxic (HC-toxin and tentoxin) or can-cerostatic activities (chlamydocin) (Scheme 8). Correspondingly, this class of compounds has been studied extensively in terms of synthesis and conformational preferences. 

Biologically active cyclic tetrapeptides (4-7) showed (1) a conformational preference in the epoxyketone moiety (2) no n -+ jt peptide bond contribution to As near 288 nm and (3) anti-octant perturbation of oxirane ring. 

Rich, D.H., Bhatnagar, P.K., Jasensky, R.D., Steele, J.A., Uchytil, T.F. and Durbin, R.D. (1978) Two-conformations of the cyclic tetrapeptide, [D-MeAlal]-tentoxin have different biological activities. Bioorg. Chem. 7 207-214. 

Rich, D.H. and Bhatnagar, P.K. (1978) Conformational studies of tentoxin by nuclear magnetic resonance spectroscopy. Evidence for a new conformation for a cyclic tetrapeptide. J. Am. Chem. Soc. 100 2212-2218. 

Four different types of ring conformations have been observed in the crystal structures of cyclic tetrapeptides and cyclic tetradepsipeptides. They are (1) a cis,trans,cis,trans conformation containing a true or approximate center of symmetry, (2) a cis,trans,cis,trans conformation with a twofold rotation axis perpendicular to the average plane of the ring, (3) an all-trans conformation with a center of symmetry, and (4) an all-trans conformation with an approximate twofold rotation axis (Fig. 4). With the assumption of planar peptide units, it has been shown theoretically that four trans peptide units cannot be closed into a ring (Go and Scheraga, 1970). Crystal structure analyses have demonstrated that some cyclic tetrapeptides do, indeed, exist in the all-trans conformations (Flippen and Karle, 1976 Karimov et al, 1976). In these cases, the peptide units deviate significantly from planarity with co values as low as 156° as compared to 180°. 

Figure 5. Conformation of dihydrochlamydocin drawn by computer with experimentally derived coordinates from crystal structure analysis. The cyclic tetrapeptide has all-trans peptide groups and two 3 1 intramolecular NH 0=C bonds. (Flippen and Karle, 1976).

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. 

Recently, Ghadiri has reported modified cyclic tetrapeptides with alterations in the peptide backbone. It was proposed that the most hioactive conformation of apicidin contains a cis amide rotamer and this was probed by incorporating a triazole isostere for the amide. The 1,5-triazole 33 (Figure 4.13) showed decreased isoform selectivity compared to apicidin, more potently inhibiting HDAC6 and HDAC8 than the natural product. 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

An interesting comparison can be made looking at the a- and (5-tetralin derivatives entries—15/16 and —17 in Table 1 which can be regarded as cyclic confor-mationally constrained analogues of phenylglycine and phenylalanine. In an interesting study, 6-hydroxy-2-aminotetralin-2-carboxylic acid 12 (Hat) has been incorporated as a conformationally constrained tyrosine analogue into S-opioid receptor selective tetrapeptides.114 15 Whereas entry 15, the (S)-a-tetralin deriva-... 

C. M. Falcomer, Y. C. Meinwald, I. Choudhary, S. Talluri, P. J. Milburn, J. Clardy, and H. A. Scheraga,/. Am. Chem. Soc., 114,4036 (1992). Chain Reversals in Model Peptides Studies of Cystine-Containing Cyclic Peptides. 3. Conformational Free Energies of Cyclization of Tetrapeptides of Sequence Ac-Cys-Pro—X-Cys-NHMe. 

Dory and co-workers synthesized a tripeptide composed of a, -unsaturated (5-amino acids (Fig. 8.10a) [45]. The trans geometry of the vinyl group was used to induce the peptide to adopt a flat conformation required for the self-assembling process. In a similar way to the nanombes from y5-peptides, the peptide backbone has an even number of atoms between the carbonyl and amino groups of each residue. As a result, all the hydrogen bonds were parallel in the nanotube (Fig. 8.10b). The same group further extended this pattern to di-, tri-, and tetrapeptides of -amino acids with a trans yS,(5-double bond (Fig. 8.10c). AU of these cyclic peptides were found to self-assemble into hydrogen bonded nanotubes [46]. 

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