Antibiotic, cyclopeptide

Cyclosporine is a macrolide antibiotic cyclopeptide with 11 amino acids. It inhibits cytokines (primarily interleukin-2) produced by T-cells in response to antigen exposure. Cyclosporin A can be biosynthesized from soil fungus Tolypocladium inflatum or synthetically manufactured. Hazardous combustion and decomposition products of this process include carbon monoxide, carbon dioxide, nitrogen oxide, hydrogen chloride gas, and phosgene. 

OH >j C02H H (both diastereomers) Bacteria -Streptomyces sp. (trans isomer is also found in Delonix regia and many collagens) Telomycin - cyclopeptide antibiotic 214, 242... 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

CNMR investigations of several cyclic and acyclic peptide antibiotics and toxins have been reported in the literature, e.g., gramicidin S-A (cyclo(Phe-Pro-Val-Orn-Leu)2) [176, 801, 872 875], viomycin (cyclopeptide constituted of L-serine, at, I-L-di-aminopropionic acid, /J-L-lysine and viomycidine) [876], bacitracin A (Ile-Cys-Leu-D-Glu-Ile-Lys-n-Orn-Ile) [815], alamethicin (Ac-Aib-Pro-Val-Aib-Val-Aib-Aib-Ala-Aib-... 

Plants containing these alkaloids have been often employed in folk medicine without however any knowledge as to a definite activity. Even the observed effects, if any, are not definitely ascribable to the cyclopeptides alone. It has been reported that Zizyphus mucronata is emplqyed by the natives of central and southern Africa in the treatment of diarrhea and dysentery. It is not impossible that such an effect may be ascribable to the alkaloids in view of their now known antibiotic... 

Fig. 7.15 Proposed mode of antibiotic action by cyclopeptides tubes (green) form and aggregate to disrupt bacterial membranes (red)...

The MALDI-TOF monitored SP preparation of lysobactin, a natural cyclopeptide antibiotic, on PS resin bearing the Rink amine linker 1.6 has been reported (141). The SPS scheme is shown in Fig. 1.21. The classical peptide coupling steps, the allyl deprotection (see Section 1.3.5), and the macrocyclization step were all monitored by MALDI-TOF, and the purity of the products was also determined using this technique. The presence of small impurities in compounds 1.56-1.61 was easily detected, and the reaction conditions for the key deprotection of 1.59 and cyclization of 1.60 were rapidly optimized. A total yield of 15% was obtained after HPLC purification of released 1.62 (lysobactin). 

S,47 ) -Hydroxypipecolic acid [(-)-a3 -4-hydroxy-2-piperidine carboxylic acid, 3] was isolated from the leaves of Calliandra piuieri and Strophantus scandeus and it was identified as a constituent of cyclopeptide antibiotics, such as virginiamycin S2. It was also employed as a precursor in the preparation of selective N-methyl-D-aspartate receptor antagonists. Furthermore, (-)-3 has served as a building block in a recent synthesis of palinavir, a potent peptidomimetic-based HIV protease inhibitor. ... 

Capreomycin, an antitubercular antibiotic isolated from Streptomyces capreolus A250 in 1960. The cyclopeptide is strongly basic. Four components, designated capreomycin lA (1), IB (2), IIA (3), and IIB (4), have been described as being produced... 

Peptide alkaloids. Alkaloids containing amino acids linked by peptide bonds examples include the er-got alkaloids and the cyclopeptide alkaloids (Rham-naceae alkaloids) as well as the amanitins and phal-lotoxins of the death cup. In spite of their structural similarities, the peptide antibiotics and /9-lactam antibiotics are not included in the peptide alkaloids. Lit. Alkaloids Chem. Biol. Perspect. 12, 187-228 (1998) Manske 26, 299-326 Zechmeister 28, 162-203. 

The P. B are cyclopeptides containing L-2,4-diamino-butanoic acid residues (Dab) and a o-amino acid col-istins A and B, which are also known as P. E, and E2, have the same basic structure. P. exert bactericidal effects on growing and resting cells by impairing the permeability of the bacterial membrane. On account of toxic side affects (nephro- and neurotoxicity) the therapeutic use of P. is limited it is mostly administered locally or orally but rarely parenterally Lit. Experientia 22,354 (1966). J. Antibiot. 30,767 (1977). Antibiotiki 16, 250 (1971). j. Antibiot. 30,427, 1029,1039 (1977). Hager (5.) 1,749f. 7,1091 9,286 ff. Kleemann-En-gel, p. 1556. 

Mr 602.73, needles, mp. 173-174°C, [o]d -63.7° (CH3OH). Cyclopeptide antibiotic from cultures of the fungus Helicoma ambiens, which shows antitumor activity. 

Amidations of vinyl iodides have also been used to advantage in synthesis. Enamides such as 50-52 are representative of the procedures available (Scheme 1-3). By proper choice of nucleophile, annulations to either pyrroles 54 (15 examples) or pyrazoles 55 (10 examples) can be induced with Cul-catalysis after an initial amidation of enyne 53. " Subsequent 5-endo-dig cyclization produces the heteroaromatic products (Scheme 1-4). Several total syntheses have successfully applied this approach, as examples, to construction of key enamide antibiotic CJ-15,801 (56), and the naturally occurring cyclopeptide alkaloid paliurine F (57), where this methodology served as a tool for macrocyclization. " ... 

One also has to consider that not aU amino add-based natural ligands are structurally so complex as a protein. There are a number of relatively low-molecular-weight natural peptides, for example, cyclopeptides, that very efQciendy and selectively interact with a complementary substrate. Notable examples are the antibiotics vaUnomycin, 1, and vancomycin, 2, as weU as the natural macrocyclic ligand patellamide A, 3 (Scheme 1). 

Numerous a,P-dehydroamino acids have in recent years been identified as constituents of fungal metabolites. Their characterization and typical structural features are summarized in Table 1. In most of these metabolites, almost all of which are cyclic compounds (cyclopeptides or cyclodepsipeptides) and which frequently possess antibiotic properties, D-amino acids also occur. 

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