Cyclopeptide

One of the types of cyclopeptides, type 3, has a seemingly restricted distribution, including only the two orders Santalales and Gentianales.

From: Comprehensive Natural Products II , 2010

Mushrooms, Cyclopeptide

S.M. Schneider , in Encyclopedia of Toxicology (Third Edition), 2014

Mechanism of Toxicity

Cyclopeptide mushrooms contain both amatoxins and phallotoxins. Studies in animals have shown that, although the phallotoxins are highly toxic when given parenterally, they are not absorbed from the gastrointestinal tract and do not produce toxicity when given orally. The toxicity of cyclopeptide mushrooms is believed to be due to the amatoxins. At least six amatoxins have been identified that differ according to amino acid substitutions on the peptide ring. Alpha- and beta-amanitins are felt to be the predominant cyclopeptides producing systemic toxicity. The phallotoxins may contribute to gastrointestinal symptoms but this is unclear. Amatoxins interfere with RNA and DNA transcription by interfering with RNA polymerase II. The liver is primarily affected.

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Synthetic Methods I – Chiral Pool and Diastereoselective Methods

J. Mulzer , in Comprehensive Chirality, 2012

2.6.8.1 Palurine F 25 (Scheme 16)

Cyclopeptide alkaloids have been isolated from a wide variety of plant species throughout the world. The interesting topology and biology of these natural products and their restricted natural availability have prompted intensive interest from the synthetic community. The synthesis of the sedative cyclopeptide paliurine F is centered around the preparation of the hydroxyprolinol derivative 16.4 from N-Boc-D-serine 16.1. Thus, 16.1 was converted into ketone 16.2 via O-silylation and addition of two equivalents of allylmagnesium bromide to the monolithium salt of the carboxylic acid. Reduction to alcohol 16.3 was followed by formation of the aldehyde which was cyclized to 16.4 via reduction of the intermediate aminal.

Scheme 16. Synthesis of 3-hydroxy-prolinol 17.4 and its use in the preparation of paliurine F (16.8).

O-Arylation under modified Ullmann conditions furnished ether 16.5, which was converted into peptide 16.6 under standard conditions. A second Ullmann type reaction served to close the macrocyclic ring under formation cyclopeptide 16.7 which was elaborated into paliurine F via peptide coupling.

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Mushrooms

JEFFREY BRENT MD, PHD , ROBERT B. PALMER PHD , in Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose (Fourth Edition), 2007

Overview

The cyclopeptide-containing mushrooms are responsible for more than 90% of all deaths due to mushroom poisonings in the Western world. These mushrooms are found predominantly throughout Europe and North America. The cyclopeptides are found mainly in species from three genera: Amanita, Galerina, and Lepiota (see Box 23-2 and Figs. 23-3 to 23-5). The vast majority of serious poisonings and fatalities in this group of mushrooms, however, result from Amanita, particularly Amanita phalloides (see Fig. 23-3). Ingestion of deadly Amanita most commonly occurs after misidentification of the mushroom by foragers, although the possibility of criminal or terrorist use of toxins isolated from Amanita species has also been suggested. 7 These mushrooms are most commonly found during the late summer or autumn in well-forested areas. The cyclopeptide toxins consist primarily of amatoxins, which contain eight amino acids, and the seven residue phallotoxins and virotoxins. More than 15 cyclopeptides have been isolated from the genus Amanita. Note, however, that not all mushrooms of the Amanita species contain significant quantities of amatoxin. Amanita muscaria and Amanita pantherina, for example, contain no amatoxin, and ingestion of these mushrooms is not associated with development of hepatotoxicity.

The phallotoxins are extremely potent hepatotoxins but are not well absorbed from the GI tract and therefore contribute little to Amanita toxicity following ingestion. They may contribute to the initial gastroenteritis-like picture, although this has also been questioned. 8 Laboratory animals cannot be poisoned by oral administration of the phallotoxin phalloidin, whereas they die within hours after intravenous injection of the same compound.

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Foodborne Disease

Rajal K. Mody , Patricia M. Griffin , in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015

Abdominal Cramps and Diarrhea within 6 to 24 Hours, Followed by Hepatorenal Failure.

Mushrooms containing cyclopeptides (amatoxins and phallotoxins) are responsible for greater than 90% of all mushroom poisoning fatalities (see Table 103-4). The most common implicated mushrooms are Amanita phalloides and Amanita virosa. 110 The illness is biphasic. Severe abdominal cramps, vomiting, and severe diarrhea present acutely and usually resolve within 12 to 24 hours. The patient then remains well for 12 to 24 hours. Two to 4 days after ingestion, hepatic and renal failure supervene. The mortality rate in adults is about 10% to 30%. 110 A similar syndrome occurs after ingestion of mushrooms containing gyromitrin. Although renal failure is not a feature, hemolysis, seizures, and coma may occur. 111

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Long-Term Implications of Antibiotic Use on Gut Health and Microbiota in Populations Including Patients With Cystic Fibrosis

J. Deane , ... B.J. Plant , in The Gut-Brain Axis, 2016

Polmyxins

Colistin sulfomethate is cyclopeptide, belonging to the family of polymyxins, which is produced by Bacillus polymyxa var. colistinus (Jeong et al., 2009; Storm et al., 1977). Colistin is mainly active against gram-negative organisms. Its mode of action involves inducing changes in the permeability of the cell wall by binding anionic lipopolysaccharide molecules and displacing calcium and magnesium, thus causing cell leakage and death (Jeong et al., 2009). Orally administered colistin is known to be poorly absorbed in the gastrointestinal tract, and studies show that when excreted it is bound to the fecal material (Eichenwald and McCracken, 1978). This may reduce the perturbation effect of the drug in vivo. Jeong et al. (2009) show that E. coli was the most susceptible to colistin. Colistin sulfomethate is one of the most frequently used antibiotics for treatment of exacerbations in CF patients. Early eradication of Pseudomonas infection with nebulized drug, aggressive treatment of acute exacerbations with intravenous therapy, and long-term suppressive maintenance therapy again nebulized are the three primary modes of usage in CF management. Colistin forms part of each of these (Littlewood et al., 2000). P. aeruginosa is known to frequently develop resistance to β-lactam antibiotics and aminoglycosides. However, thus far in vitro resistance of Pseudomonas species to colistin is rare, cementing its place as a useful treatment for pseudomonal infections for the foreseeable future. Wright et al. (2013) have shown using in vitro culture methods that antibiotics (ceftazadime, colistin, azithromycin, and tobramycin) at subinhibitory concentrations result in the phenotypic population diversification of P. aeruginosa. It is interesting to note that they demonstrated that ceftazadime and colistin contributed to more diversification than tobramycin and azithromycin. Diversification of the P. aeruginosa populations in the CF lung negatively affect antibiotic therapy success, leading to a chronic infection state and ultimately to progression of the disease. Whether this diversification pressure is also exerted on taxa in the gut has not been reported. Knowledge of differential diversification potential of antibiotics can contribute to more informed decisions for antibiotic selection in management and control of infection.

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Mechanisms of action

Françoise Van Bambeke , ... Paul M. Tulkens , in Infectious Diseases (Third Edition), 2010

Other agents acting on the cell membrane and cell wall synthesis

Daptomycin is a cyclic peptide flanked by an oxodecyl side chain conferring a strong amphiphilic character to the molecule (molecules in this group are often referred to as lipopeptides or peptolides; this erroneously suggests high lipophilicity, which is not true for daptomycin since the octanol–water partition is actually quite negative).

Daptomycin is used against vancomycin-resistant enterococci for staphylococcal infections. It has a novel mode of action, in that the molecule binds to Ca2+ to form an oligomeric assembly with the lipid tails pointing inwards. The loose micelles serve to deliver daptomycin to the bacterial membrane in a 'detergent-like' form, causing leakage of cytosolic contents and a rapid bactericidal effect (Fig. 130.7). 12 Daptomycin is only active against Gram-positive bacteria since it cannot cross the outer membrane of Gram-negative organisms. Daptomycin shows preferential interaction with the phospholipid, phosphatidylglycerol, which is abundant in prokaryotic cell membranes and largely absent from eukaryotic cell membranes, except in lung surfactant where it forms aggregates, thereby explaining the failure of daptomycin in treating pulmonary infections.

Resistance to daptomycin has already been described, resulting from mutations in genes that encode enzymes involved in the synthesis of phosphatidylglycerol. Staphylococcus aureus with a VISA phenotype (see glycopeptides section) are less susceptible to daptomycin due to impaired access through the thickened cell wall. 9

Daptomycin activity is concentration dependent, whereas its toxicity (mainly for skeletal muscle) is more related to the frequency of exposure. As a result, daptomycin should be administered once daily. The original dose during development was 4   mg/kg. Whether this will be sufficient for difficult-to-treat staphylococcal infections and can be increased without eliciting unacceptable toxic reactions requires further study.

d-Cycloserine is a broad-spectrum antibiotic which has structural similarities to d-Ala (see Fig. 130.2; Fig. 130.8) and inhibits the conversion of l-Ala into d-Ala (catalyzed by a racemase) and the dimerization of d-Ala (catalyzed by the d-Ala:d-Ala ligase). 13

Fosfomycin, which bears structural similarities to phospho-enol-pyruvate, inhibits very early stage synthesis of peptidoglycan by impairing the formation of uridine diphosphate (UDP)-N-acetylglucosamine-enol-pyruvate, a precursor of UDP-N-acetylmuramic acid (see Figs 130.2, 130.8). 14

Bacitracin is a polypeptide of complex structure. It acts as an inhibitor of peptidoglycan synthesis at the level of translocation of the precursor across the bacterial membrane (see Fig. 130.2). 15

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Cyclosporine

Sahil Sekhon , ... John Y.M. Koo , in Comprehensive Dermatologic Drug Therapy (Fourth Edition), 2021

Structure

CsA is a neutral cyclic peptide composed of 11 amino acids (Fig. 17.1). It is available in original formulation (Sandimmune) or in a more consistently bioavailable microemulsion formulation (Neoral, Gengraf). Neoral is the only formulation of CsA that is approved for the treatment of psoriasis. Neoral is available in capsules or as an oral solution. The oral solution contains 100 mg/mL and should be diluted, preferably with orange juice or apple juice, immediately before it is administered, to make it more palatable. Grapefruit juice affects the metabolism of CsA and should be avoided. The soft gelatin capsules are much more convenient and are available in 25- and 100-mg strengths.

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Gastrointestinal Hormones and Neurotransmitters

Rodger A. Liddle , in Sleisenger and Fordtran's Gastrointestinal and Liver Disease (Ninth Edition), 2010

SOMATOSTATIN

Somatostatin is a 14–amino acid cyclic peptide that was initially identified as an inhibitor of growth hormone secretion. Since its discovery, it has been found in almost every organ in the body and throughout the GI tract. In the gut, somatostatin is produced by D cells in the gastric and intestinal mucosa and islets of the pancreas, as well as enteric neurons. 68 Somatostatin has a number of pharmacologic effects that are mostly inhibitory.

In the stomach, somatostatin plays an important role in regulating gastric acid secretion. 69 In the antrum, D cells are open to the lumen, where they are directly exposed to acid. A low gastric pH stimulates D cells that lie in close proximity to gastrin-producing cells to secrete somatostatin and inhibit gastrin release (see Chapter 49). Reduced gastrin secretion decreases the stimulus for acid production and the pH of the stomach contents rises. Thus, some of the inhibitory effects of gastric acid on gastrin release (see earlier, "Gastrin") are mediated by somatostatin.

Somatostatin release is also influenced by mechanical stimulation, dietary components of a meal, including protein, fat, and glucose, and other hormones and neurotransmitters. 70 Muscarinic stimulation appears to be the most important neural stimulus to somatostatin secretion.

At least five somatostatin receptors have been identified that account for divergent pharmacologic properties. 71 For example, receptor subtypes 2 and 3 couple to inhibitory G proteins but receptor subtype 1 does not. In addition, only somatostatin receptor subtype 3 inhibits adenylate cyclase. The inhibitory effects of somatostatin are mediated by a decrease in cAMP, Ca2+ channel inhibition, or K+ channel opening.

In the gut, somatostatin has broad inhibitory actions. In addition to effects on gastric acid, somatostatin reduces pepsinogen secretion. Somatostatin profoundly inhibits pancreatic enzyme, fluid, and bicarbonate secretion and reduces bile flow. 72 The effects of somatostatin on gut motility are largely inhibitory, with the exception that it stimulates the migrating motor complex, possibly through effects on motilin. Somatostatin also reduces intestinal transport of nutrients and fluid, reduces splanchnic blood flow, and has inhibitory effects on tissue growth and proliferation. 73,74

Because of its varied physiologic effects, somatostatin has several clinically important pharmacologic uses. Many endocrine cells possess somatostatin receptors and are sensitive to inhibitory regulation. Therefore, somatostatin and more recently developed somatostatin analogs are used to treat conditions of hormone excess produced by endocrine tumors, such as acromegaly, carcinoid tumors, and islet cell tumors (including gastrinomas). 75 Its ability to reduce splanchnic blood flow and portal venous pressure has led to somatostatin analogs being useful in treating esophageal variceal bleeding (see Chapter 90). 76 The inhibitory effects on secretion have been exploited by using somatostatin analogs to treat some forms of diarrhea and reduce fluid output from pancreatic fistulas. Many endocrine tumors express abundant somatostatin receptors, making it possible to use radiolabeled somatostatin analogs, such as octreotide, to localize even small tumors throughout the body.

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Nitrogen-Containing Macrocycles Having a Carbohydrate Scaffold

Mykhaylo A. Potopnyk , Sławomir Jarosz , in Advances in Carbohydrate Chemistry and Biochemistry, 2014

1 C 2-Symmetrical Macrocyclic Glycopeptides

Kessler developed a synthesis of C 2 -symmetrical cyclopeptides containing (α- d-glucopyranosyluronic acid)methylamine alternating with different α-amino acids (Gly, l-Ala, d-Ala, l-Phe, d-Phe, l-Lys, or d-Lys). Coupling of the N-Fmoc-(Bn)3-protected uronic acid derivative 206 with amino acids fixed on the polymer (207), followed by Fmoc-deprotection, gave products 208. Chain elongation and removal from the resin provided linear tetrapeptide analogues (209), which cyclized further to macrocyclic glycopeptides 210, finally converted into the debenzylated product 211 (Scheme 38). 121 Similar methodology was used for the preparation of a C 2-symmetrical macrocyclic glycopeptide (212). 122

Scheme 38. Synthesis of C 2-symmetrical macrocyclic glycopeptides 210–212.

Nilsson and Billing prepared macrocyclic octapeptide analogues containing a pyranoid "d-sugar amino acid." Methyl 3,4-di-O-benzoyl-2-(9-fluorenylmethoxycarbonyl)amino-2-deoxy-β-d-glucopyranoside (213) was oxidized at C-6 with the Jones's reagent and the crude product 214 was coupled directly with the C-protected tripeptide tert-butyl esters 215a–c [H-(Tyr)3-O t Bu, H-Tyr-Glu(OBzl)-Tyr-O t Bu or H-Tyr-Arg(Mtr)-Tyr-O t Bu] providing "sugar amino acid"–amino acid hybrids 216a–c (Scheme 39). 123

Scheme 39. Synthesis of compounds 216a–c.

N-Deprotection of 216a–c afforded the amino derivatives 217a–c, whereas C-deprotection gave carboxylic acids 218a–c. Coupling of 217a–c with 218a–c afforded linear dimers 219a–c. Cleavage of the fluorenylmethoxycarbonyl protecting group and hydrolysis of the ester function furnished amino acid derivatives 220a–c. Intramolecular head-to-head macrocyclization provided the C 2-symmetrical macrocycles 221a–c. Final deprotection of these derivatives afforded the macrocycles 222a–c (Scheme 40), which bound (K a  ~   10   M−   1) to certain purine nucleotides, including 2′-deoxyadenosine 5′-monophosphate (dAMP) and 2′-deoxyguanosine 5′-monophosphate (dGMP). 123

Scheme 40. Synthesis of macrocycles 222a–c.

These authors also developed a convenient method for the preparation of C 2-symmetrical macrocyclic carbohydrate–amino acid hybrids through a Cu(I)-catalyzed formation of 1,2,3-triazole linkages. Acids 224a,b were coupled with the azido-amino sugar 223, providing propiolyl-dipeptideazidoamino sugar hybrids 225a,b which—under the "click conditions"—underwent cyclodimerization to C 2-symmetrical compounds 226a,b finally converted into the free deprotected derivatives 227a,b (Scheme 41). 124

Scheme 41. Synthesis of C 2-symmetrical macrocyclic compounds 227a,b.

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Synthesis and Structure-Activity Studies of Lissoclinum Peptide Alkaloids

Peter Wipf , in Alkaloids: Chemical and Biological Perspectives, 1998

4 SECONDARY STRUCTURES OF LISSOCLINUM PEPTIDE ALKALOIDS

Upon introduction of five-membered heterocycles into the cyclopeptide sequence, the conformationally flexibility of the 18-24 membered macrocycles is considerably reduced, and mostly a single secondary structure is preferred in the solid state and in solution. Accordingly, a better understanding of the effects of amino acid-derived thiazoline and oxazoline heterocycles on the conformation of cyclopeptides can facilitate the de novo design of 3-dimensionally preorganized macrocycles.

Structural analysis of lissoclinum peptides has focused almost exclusively on 18- and 24- membered macrocycles. These derivatives assume molecular "triangle", "square", and "twisted eight" conformations in solution and the solid state.

No detailed conformational analyses of the solution structure of 18-membered lissoclinum peptides by NMR methods have been published. However, several solid state conformations are known from x-ray analyses. Cycloxazoline (westiellamide, 5) shows a typical planar ring with less than 1   Å deviation from planarity [5]. Noteworthy is the disposition of the peptide N-H groups into the ring, and the peptide carbonyl functions toward the outside, which places the valine isopropyl side chains into an axial arrangement (Figure 5). A molecular dynamics simulation of bistratamide C established an analogous planar three-dimensional structure for 3 [4]. Since the x-ray analysis of the closely related nostocyclamide (10) also showed a planar macrocycle with a maximum deviation of any backbone atom from its ring plane of less than 0.2   Å (Figure 6, [10]), one can conclude that irrespective of the oxidation state of the azoles and the nature of the side chain substituents, 18-membered lissoclinum peptides have a strong preference for a planar, porphyrin-like macrocycle geometry with all nitrogen atoms oriented toward the center of the molecule.

Figure 5. Stereoview of the x-ray structure of cycloxazoline (westiellamide, 5) [5].

Figure 6. Stereoview of the x-ray structure of nostocyclamide (10) [10].

Considerable information about solution and solid state conformations of 24-membered lissoclinum peptides is available. Most prominent is a distorted "molecular square" or saddle-shaped conformation with heterocycles placed at the corners of the rectangle. All nitrogen atoms are positioned at the inside of the ring in this conformation, and carbonyl groups are pointing outwards. This motif is illustrated by x-ray structures of ascidiacyclamide (22) [85–87] and patellamide A (23) [88, 89] (Figures 7 and 8). The pseudo-axial attachment of the side-chains on the macrocycle is clearly visible in the stereoviews. The C2-symmetric structure for 22 and 23 observed in the crystal appears to be essentially the same as the solution structure based on NMR experiments [86]. The solvent interaction with H2O, EtOH, and benzene has been studied for ascidiacyclamide [87]. Very similarly, patellamide A also displays a saddle-shaped rectangular form wrapped around the H2O and MeOH solvent molecules (Figure 8) [88, 89]. The typical pseudo C2-symmetric square was also shown by 1H NMR analysis to be predominant for ulithiacyclamide in solution in nonpolar solvents [90]. This group of 24-membered lissoclinum peptides resembles therefore most closely the conformation of the 18-membered macrocycles. At least ulithiacyclamide, however, is thought to undergo some conformational change at the amide groups in a more polar DMSO solution [90].

Figure 7. Stereoview of the x-ray structure of ascidiacyclamide (22) [85].

Figure 8. Stereoview of the x-ray structure of patellamide A (23) [88, 89].

In a drastic departure from the conformations observed for ascidiacyclamide, patellamide A, and ulithiacyclamide, the x-ray structure of patellamide D (26) shows a severely folded, twisted "figure eight" backbone (Figure 9) [14]. Four transannular hydrogen bonds stabilize this compact geometry, and only the phenylalanine side chain protrudes away from the backbone, whereas the isoleucine side chain clusters onto the macrocycle. The isoleucyloxazoline segments form a pair of type II β-turns [91] stabilized by intramolecular hydrogen bonding. Two additional hydrogen bonds are formed between the isoleucine amide nitrogens and the oxygen atoms of the oxazoline rings. The two thiazole rings are oriented nearly parallel, with a separation distance of 4.1   Å.

Figure 9. Stereoview of the x-ray structure of patellamide D (26) [14].

The distinctly different solid state conformation of patellamide D compared with that of ascidiacyclamide and patellamide A demonstrates that there are at least two preferred conformations for 24-membered lissoclinum peptides. A decrease in the C2-symmetry of the macrocycle has been suggested as responsible for a transition from the "molecular square" to the "twisted eight" conformation [88, 92]. Patellamide D contains a phenylalanine residue opposite an alanine residue, whereas ascidiacyclamide is completely symmetrical. In patellamide A, the only deviation from C2-symmetry is the replacement of a threonine-derived (C(4) methylated) oxazoline with a serine-derived (C(4) unsubstituted) oxazoline. Patellamide B and C, which also have non-C2-symmetrical side chain substituents, were recently shown to have twisted solution conformations that resemble patellamide D [92]. An alternative interpretation focuses on the steric properties of β-branched amino acid side chains [93]. Both ascidiacyclamide and patellamide A contain exclusively β-branched valine and isoleucine amino acid building blocks, whereas patellamides B, C, and D have two isoleucines or valines next to alanine and phenylalanine residues. The severe steric hindrance induced by β-branched side chains prevents collapse of the macrocycles into the 'twisted eight' conformation [93]. In ulithiacyclamide, the disulfide bridge prevents the hydrophobic collapse sterically in a related fashion. The exclusive presence of β-branched amino acid side chains appears to be a stringent requirement for 'molecular square'-like geometry. Tawicyclamide B (31), which lacks this feature, assumes the familiar 'twisted-eight' conformation (Figure 10) [32]. Interestingly, upon oxidation of the thiazoline ring to the thiazole, the valine-proline amide bond isomerizes from cis to trans [32].

Figure 10. Stereoview of the x-ray structure of tawicyclamide B (31) [32].

One of the major attractions of lissoclinum peptides is the use of their unique structural features for the design of conformationally preorganized peptide and peptidomimetic sequences. Oxazoline and thiazoline heterocycles impose considerable conformational restrictions onto the macrocycles. A recent 2D NMR study has demonstrated that conversion of two cysteine residues in the flexible cyclooctapeptide c[Ile-Thr-D-Val-Cys-Ile-Thr-D-Val-Cys-] (a sequence derived from ascidiacyclamide) results in a single, pseudochair solution conformation [94]. Conversely, rearrangement of the two threonine residues in this sequence to amino esters (in practice, this compound was obtained by hydrolysis of ascidiacyclamide), provides a more shallow, less constrained pseudo-boat conformation than ascidiacyclamide itself [94]. An x-ray structure of the potassium complex of the amino ester is shown in Figure 11 [95].

Figure 11. Stereoview of the x-ray structure of ascidiacyclamide hydrolysis product-potassium complex [95].

The almost symmetrical array of oxazolines, oxazoles, thiazolines, and thiazoles in lissoclinum macrocycles is reminiscent of ring-extended porphyrins [96] and aza-crown ethers [97] and has nurtured considerable speculation about potential metal-ion chelation properties of these natural products [98]. The fundamental validity of this hypothesis has been confirmed by the characterization of three metal complexes of lissoclinum peptides to silver(I) and copper(II) ions. Cycloxazoline (westiellamide, 5) binds silver cations strongly and selectively over Cu(I), Cu(II), Hg(II), Co(I), and other metal ions [99]. In the solid state and in solution, an unprecedented sandwich complex is formed which stabilizes a cluster of four silver cations (Figure 12). Noteworthy here is also the conformation of die macrocyclic rings compared to the unchelated structure shown in Figure 5: Upon binding to Ag(I), the macrocycle flips inside-out with carbonyl groups pointing toward the center of the molecule and side chains positioned in a pseudo-equatorial orientation. This conformational switch reveals another interesting feature of lissoclinum peptides, i.e. the possibility to induce transitions between well-defined conformational states by external binding events. Since the association constant for formation of the cycloxazoline-silver cluster averages 2.8 × 1013  M-   5 in d4-methanol/D2O (9:1), the lack of conformational organization does not appear to be detrimental to tight, selective binding.

Figure 12. Stereo view of the x-ray structure of [(cycloxazoline)2Ag4](ClO4)4 complex [99].

A greater degree of preorganization of the parent macrocycle toward metal ion chelation is shown in the crystal structure of the bis(copper(II)) complex of ascidiacyclamide (Figure 13) [100]. The presence of a bridging carbonate in the complex is remarkable and offers the intriguing possibility that a biological function of the natural product might involve CO2 transport [100]. The detailed characterization of a related copper(II) patellamide D complex has been complicated by the occurrence of several solution equilibria [101].

Figure 13. Stereoview of the x-ray structure of a biscopper ascidiacyclamide complex [100].

It is clear from the present data that the lissoclinum peptide alkaloids provide a fascinating range of structural features that might well become useful for the design of conformationally preorganized macrocycles or linear strands with tailored physical or biological properties. Among areas for future investigations, the exploration of conformational switches and the determination of the structural characteristics of 21-membered lissoclinum peptides appear particularly attractive.

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