Bicyclic peptides

Poisoning and sometimes death from eating (unidentified) mushrooms is well known. In particular, Amanita sp. are particularly dangerous, with much emphasis on the death cap fungus , Amanita phalloides.24 The best known toxins are the amatoxins and phallotoxins, which are complex, bicyclic peptides. An unusual feature relates to sulfur a tryptophan (or substituted tryptophan) unit is linked to a cysteine sulfur at the carbon atom next to the NH group of the pyrrole ring, forming the unit, -CH2-S-C(NH)=C, e.g. in... 

Labeled phallotoxines (phalloidins) The bicyclic peptides isolated from Amanita phalloides mushroom bind selectively to F-actin in nanomolar concentrations. They have advantages over antibodies for actin labeling... 

In a number of laboratories macrocyclic peptides have been studied as enzyme models 47,63, 70, 72a, 91). A bicyclic peptide (17) with considerable apolar character was made by Murakami et al. (70) in which Hex is 6-amino-hexanoyl Und is co-aminoundecanoyl. The esterolysis of p-nitrophenyl carboxylates by (17) was studied over the pH range 10-12. The rate depends on the ionization of one group (pK 12.3), which is apparently the anionic imidazole group. 

The phallotoxins, phalloidin and phallacidin, are bicyclic peptides with mol wts of 789 and 847 Dalton, respectively. The NBD phallacidin and rhodamine phalloidin conjugates have been most frequently utilized in flow cytometric assays. The fluorescent phallotoxin conjugates have mol wts of 1000-1200 Dalton, are water-soluble, and stain actin at nanomolar concentrations (reviewed in ref. 19). Unconjugated phallotoxins should be obtained to verify the specificity of fluorescent phallotoxin staining to F-actin (see Note 4). 

In the following discussion a selection of optimized procedures is presented for the synthesis on solid support of homodetic monocyclic and bicyclic as well as mixed homodetic/ heterodetic bicyclic peptides that contain at least one lactam ring, whereas heterodetic cyclic peptides containing other than amide bonds or peptidomimetics are not discussed here because of their unlimited diversity. 

The bicyclic peptides that have been synthesized with at least one lactam ring correspond to the structures shown in Scheme 22, and examples of such syntheses of homodetic or mixed homodetic/heterodetic structures are listed in Table 12. For bicyclic or polycyclic cystine peptides see Sections 6.1 and 6.2. In the ring structures of types I-III both rings derive from side-chain-to-side-chain cyclizations. In the structures of types IV-VI an cofunctionalized amino acid is employed as bridgehead. This can be linked directly to three... 

Scheme 22 Various Types of Bicyclic Peptides Synthesized on Solid Supports...

The synthesis of type I bicyclic peptides is the most simple as the two side-chain-to-side-chain cyclizations can be performed successively on the assembled peptide or more appropriately by condensation of the two monocyclic segments preferably in solution. As shown in Scheme 23 (path A), for the synthesis of suitably protected monocyclic peptides, side-chain attachment of Asp or Glu residues to the oxime resin is proposed,[436,43T which leads to the desired cyclization and release of the protected segments as Pac or preferably as A1 es-tersJ396 These are C-terminally deprotected, when required, and then assembled in solution into bi- or polycyclic peptides of type I. 

Similarly, the mixed homodetic/heterodetic bicyclic structures containing a disulfide bridge are preferably produced as monocyclic compounds that are then typically oxidized in solution adopting standard procedures as described in Section 6.1.1 (Scheme 23, path Bl). If even disulfide formation is performed on resin by the procedures reported in Section 6.1.2, an additional level of selective protection is required for the cysteine thiol functions. The synthetic paths Bl and B2 are also applicable for the synthesis of type II and III bicyclic peptides, independent of whether only lactam bridges are produced or mixtures of lactam/ disulfide bridges. 

Table 12 Selected Bicyclic Peptides That Represent the Six Types of Bicyclization Shown in Scheme...

Great attention has been paid to the excellent metal-complexation properties of cyclic peptides. 1 615 631 Naturally occurring examples include enniatin, valinomycin, 616 or antama-nide, 316 and cyclosporin A. 632 Several libraries of cyclic peptides have been synthesized to address these properties, 402 but also bicyclic peptides have been synthesized in this context. t617-620 ... 

The experimental results on the various samples may be summarized as follows (i) The excited electronic state absorption decays rapidly on the time-scale of pico- or subpicoseconds, (ii) Longer lasting absorption changes are observed in spectral ranges with chromophore absorption for the cyclic and bicyclic peptides, (iii) Infrared experiments have clearly shown that absorption transients in the pico- to nanosecond range occur. They monitor directly structural change of the peptide backbone. 

The shape of the CD spectrum, at pH 7.0 and 25 °C, of the bicyclic peptide indicates a high degree of helical structure although the intensities of the negative maxima are less than expected for an a-helical peptide.11651 NMR studies remain to be done to characterize the helix that is stabilized by the bis(Ampa)-bridged peptide. 

Matsunaga S, Fusetani N (1995) Theonellamides A-E, Cytotoxic Bicyclic Peptides, from a Marine Sponge Theonella sp. J Org Chem 60 1177... 

Over half of the compounds reported for lithistid sponges were isolated from Theonella (family Theonellidae). Theonella species have been reported to contain a wide variety of cyclic and linear peptides and polyketides, as well as 3-alkyl piperidine derivatives nearly identical to those reported from the order Haplosclerida.58 There is also a single report of cyano- and isothiocyano-sesquiter-penes similar to those isolated from Axinellidae (order Halichondrida).42 Bewley et al. performed a cellular localization study on Theonella swinhoei in which several types of microorganisms were separated from the sponge cells. Chemical analysis of the extracts from the separated cells indicated that the bicyclic peptide theopalauamide was found exclusively in filamentous bacteria while the polyketide swinholide A was localized to a mixed population of unicellular bacteria.59... 

Synthesis of Bicyclic Peptide 9 an Alkene-bridged Mimic of the Vancomycin C-D-E Cavity... 

Starting material for the bicyclic peptide 22a of desired configuration are the amino acid building blocks 15 and 16, and the dipeptide 19, shown in Scheme 5. 

In the bicyclic peptide phalloidine where there are three eligible hydroxyl groups, one /3-hydroxyl in a threonine residue, and a y- and 5-hydroxyl group in the 7,5-dihydroxy-L-leucine residue, the controlled action of sulfuric acid leads to formation of the y-lactone only with selective cleavage of one peptide bond (Wieland and Schopf, 1959). 

Figure 1 A Scaffolded Positional-Scanning Peptide Library Built on a Bicyclic Peptide TemplateP " ...

Fig. 44. Principle of sandwich complex formation of a cystin-bridged bicyclic peptide with a cation, Z.

Theonella sp. collected off Hachijo-jima Island [30]. Theonellamide F (35) is a bicyclic peptide containing twelve aminoacids. In this cyclic peptide a dehydroalanine residue is masked by intramolecular Michael addition, giving rise to the elaborate and unprecedented histidino-alanine bridge. Further separation of the antifungal fraction of the sponge extract afforded five related peptides, theonellamides A-E [31]. Theonellamide A... 

Tachyplesins, bicyclic peptides containing 16 to 18 residues from the horseshoe crab. They are processed from a 77-residue precursor protein. Tachyplesin... 

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