Peptidic macrocycles peptides

Conceptually the most simple syntheses of complex molecules involve the joining of structural units in which all functional groups and all asymmetric centres are preformed. This technique can usually only be applied to compounds in which these units are connected by —C—X— bonds rather than C—C. It is illustrated here by the standard syntheses of oligonucleotides, peptides, and polydentate macrocyclic ligands. 

Macrocyclic peptides and depsipeptides ( macrocyciic peptides with amide and ester linkages) are important natural compounds. They have been synthesized in low yield from open-chain precursors by DCC treatment at high dilution (E. SchrSder, 1963 M.M. Shemyakin,... 

Eunctionalized supramolecular systems based on monolayers of bioactive compounds (macrocyclic ionophoric peptides, crown ethers, nucleoside derivatives) 98MI12. 

Macrocyclic peptides as antibacterial glycopeptide antibiotics 98KGS1605. 

Investigation of immune recognition segments in presynapsis and postsynapsis neurotoxins (macrocyclic peptides) 98KPS22. 

Structural determination of macrocyclic peptides cyclosporins by mass spectrometry 97CLY2. 

Vancomycin, ristocetin A and teicoplanin are produced as fermentation products of Streptomyces orientalis, Nocardia lurida and Actinoplanes teichomyceticus, respectively. All three of these related compounds consist of an aglycone basket made up of fused macrocyclic rings and pendant carbohydrate moieties (Fig. 2-1). The macrocycles contain both ether and peptide linkages. The aglycones of vancomycin and teicoplanin contain two chloro-substituted aromatic rings, while the analogous portion of ristocetin A contains no chloro substituents. 

The macrocyclization of a peptide was carried out by nucleophihc substitution on a fluorobenzene by the sulfide group of the terminal cysteine of a pentapeptide [164]. The peptide 261 was prepared by standard SPPS and was cyclized under microwave irradiation at 50 °C for 10 min in DMF (Scheme 96). The yields of 262, after cleavage with TFA, were remarkably high for a macrocyclic peptide (70%) and also the resulting HPLC purity was very high. 

Adamantane can be used to construct peptidic scaffolding and synthesis of artificial proteins. It has been introduced into different types of synthetic peptidic macrocycles, which are useful tools in peptide chemistry and stereochemistry studies and have many other applications as well. Introduction of amino acid-functionalized adamantane to the DNA nanostmctures might lead to construction of DNA-adamantane-amino acid nanostmctures with desirable stiffness and integrity. Diamondoids can be employed to constmct molecular rods, cages, and containers and also for utilization in different methods of self-assembly. In fact, through the development of self-assembly approaches and utilization of diamondoids in these processes, it would be possible to design and constmct novel nanostmctures for effective and specific carriers for each dmg. 

Kopp, F. and Marahiel, M.A. (2007) Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis. Natural Product Reports, 24, 735. 

The activity of PK and NRPSs is often precluded and/or followed by actions upon the natural products by modifying enzymes. There exists a first level of diversity in which the monomers for respective synthases must be created. For instance, in the case of many NRPs, noncanonical amino acids must be biosynthesized by a series of enzymes found within the biosynthetic gene cluster in order for the peptides to be available for elongation by the NRPS. A second level of molecular diversity comes into play via post-synthase modification. Examples of these activities include macrocyclization, heterocyclization, aromatization, methylation, oxidation, reduction, halogenation, and glycosylation. Finally, a third level of diversity can occur in which molecules from disparate secondary metabolic pathways may interact, such as the modification of a natural product by an isoprenoid oligomer. Here, we will cover only a small subsection of... 

TE-catalyzed cyclization is not limited to the synthesis of macrocyclic peptides by catalyzing the formation of aC N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a di-domain excised from fengycin synthase was... 

Kohli, R.M., Burke, M.D., Tao, J. and Walsh, C.T. (2003) Chemoenzymatic route to macrocyclic hybrid peptide/ polyketide-like molecules. Journal of the American Chemical Society, 125, 7160-7161. 

The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

Scheme 7.32 Microwave-mediated thioalkylation to prepare precursors for macrocyclic peptide synthesis.

The examples summarized in Table 5 and in Sect. 5 of this review illustrate the applicability of RCM to the preparation of various macrocyclic perfume ingredients [30], pheromones [30], antibiotics [31-35], crown ethers [36], cyclic peptides [37],catenanes [38] and capped calixarenes [39]. 

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