Peptide macrolactone

Antibiotics of the streptogramin family are an association of two groups of molecules the group A components are polyunsaturated macrolactones and the group B components are peptidic macrolactones (depsipeptides). The different members of each group differ in some substituents, functional moieties or amino-acid residues (see Sects. 4.1 and 5.1). 

Spectra of pristinamycin and related compounds have been described in two reviews [1, 2] and in papers concerning structural elucidation of these peptidic macrolactones (see Sect. 4.1.2). NMR studies on the solution conformation of pristinamycin have been reported (see Sect. 4.1.4). Due to the presence of the hydroxypicolinic acid moiety, these molecules are fluorescent (406 nm emission maximum for a 342 nm excitation maximum) and this property has been used for studying the binding of pristinamycin to ribosomes [36]. 

Synthetic approaches in the field of peptide macrolactones have been basM upon classical peptide coupling to form a linear peptide and subsequent cyclization by formation of either the ester or amide bonds. For example, both these approaches have been successfully employed for the synthesis of the peptide macrolactones belonging to the actinomycin class of antibiotics [46, 47, 48, 49, 50]. 

It should be noted that TE-catalyzed cyclization is not Umited to the synthesis ofmacrocycUc peptides by catalyzing the formation of a C—N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a didomain excised from fengydn synthase was able to catalyze the formation of a macrolactone through the formation of a C—O bond [39]. Several cyclases from PKSs have also been characterized to be functional. For example, when a TE from picromycin synthase was fused to an erythromycin module (DEBS module 3), the resulting hybrid was able to convert a diketide and 2-methylmalonyl-CoA to a triketide ketolactone (Scheme 7.12) [40]. However, their in vitro activity is in... 

Dicyclohexylcarbodiimide (DCC) is a well known reagent for peptide bond formation. It is also a useful activator for macrolactonization. However, DCC alone does not give satisfactory results. Boden and Keck [49] found that the combination of DCC and a projwr base, normally DMAP, works perfectly. Hanessian et al. [50] used the DCC-DM AP system in the synthesis of the antibiotic ( + )-avermectin B (86). As shown in Scheme 28, macrolactone 55 was obtained... 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

The greater stability of 120 relative to 123 induced us to center our efforts on luzopeptin E2. It seemed logical to examine first a macrolactonization strategy involving cyclodimerization of 125, because we estimated that the coupling of acid 124 with amine 49 would not be subject to the stereochemical difficulties alluded to in the introduction, and that no base treatment would be necessary subsequent to the union of 124 and 49 through peptide bond formation. Recall that peptides incorporating mhv are base-sensitive this property was likely to be carried over into 125. 

Masamune et al. [53] and Corey et al. [54] explored phosphorus-based reagents such as diphenylchlorophosphate 38 [55], Palomo s reagent 39 [56], PyBroP 40 [57], and PyBOP 41 [58] in macrolactonization (Figure 6.14). Peptide coup-Hng agents of carbodiimide class, such as 42a,b, also were explored by Boden and Keck [59] as activators for macrolactonization with DMAP as a base (Figure 6.14). 

Data in the literature show that the secondary metabolites of hadromerid sponges show few significant differences from those of the Astrophorida. There are a few halogenated or sulfated molecules, peptides, depsipepti-des and especially macrolactones (macrolides) in the genera Latrunculia and Spirastrella. These have led to the discovery of an important family of antitumor substances. 

Siliquariaspongia°, Theonella Macrolactones, atypical sterols, linear and cyclic peptides, cyclic depsipeptides, nitrogen-containing sesquiterpenes, pyridine derivatives, acetylenic derivatives, phosphorus derivatives analogues of calyculin, tetramic acid glycosides... 

Callipelta, Reidispongia Peptides, cyclic depsipetides, macrolactones... 

A-nor-Sterols and A-nor-stanols cyclic peptides and macrolactones nitrogen-containing diterpenes (-NC,... 

Aplysia 260 Terpenes and halogenated terpenes, halogenated cyclic ethers, peptides and cyclic depsipeptides, macrolactones, alkaloids... 

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