Hexadepsipeptide

Enniatin B is a cyclic hexadepsipeptide the smaller ring results in a relatively planer array of ligetnding oxygen atoms the more open lnd more flexible cage results in a IC Na discrimination of only 3 1 (j6). 

While the aforementioned lonophores are Streptomyces metabolites, the crown polyethers. the depicted prototype of which is dlcyclohexyl-18-crown-6, are synthetic W. Although they lack the intricate conformations of the natural lonophores arising from multiple asymmetric carbon atoms, their molecular llgeindlng properties are analogous. While they are less efficient ion carriers, their lack of labile linkages confers Increased chemical stability they find extensive use in org inlc synthesis for solubilizing electrolytes, e.g. K enolates, in nonpolar solvents thereby providing reactive naked anions ( ). 

The lonophores thus far described lack lonlzable groups and are collectively classified as neutral lonophores their complexes acquire the net charge of whatever ion is complexed. We shall now examine two representatives of the carboxylic subclass of lonophores. Only the anionic form of these lonophores complex cation hence they form electrically neutral zwitterlonic complexes. This distinction is fundamental for explaining the profound differences in biological behavior of the lonophore subclasses, hence we prefer carboxylic lonophore to the term polyether antibiotic used by Westley O). The latter term, furthermore, leads to functional ambiguity with the ethereal macrolide nactlns and crown polyethers which are neutral lonophores. 

The tail portion of nlgerlcln closely resembles monensin, however, an additional tetrahydropyranol ring thrusts the head carboxyl group into the complexation sphere. Thus, in addition to the induced dipole ion bonds previously described, nigericin complexes feature a true ionic bond. Despite major similarities in structure, nigericin prefers K over Na by a factor of 100 while monensin prefers Na over ld by a factor of 10 (11),  

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

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Valinomycin and the Enniatins. Neutral ionophores such as the cycHc dodecadepsipeptide valinomycin [2001-95-8] C H QN O g, (Fig. 8) from StreptomjcesJulvissimus (179), and the cycHc hexadepsipeptides enniatin [11113-62-5] and beauvericin [26048-05-5] from fungi (180—182),... 

The enniatins enniatin A [2503-13-17, C gH N Og, enniatin B [917-13-5] C23H yN202, enniatin C [19893-23-3], C Hg N Og, and beauvericin (Fig. 8) are 700—800 molecular weight cycHc hexadepsipeptides. They form valinomycinlike hydrophilic cavities surrounded by outer lipophilic regions, but they have more flexible stmctures than those seen with valinomycin and therefore have less specificity for potassium over sodium ion than valinomycin (186,187). 

Resistance to streptogramin type B antibiotics can be mediated in staphylococci and enterococci by plasmids carrying a vgb gene [2]. The Vgb enzyme is a lyase that linearizes the cyclic hexadepsipeptide by cleavage of the ester bond via an elimination reaction. 

The enniatins and beauveracin are cyclic hexadepsipeptides and so are 18-membered macrocycles built up of alternating amino acid and carboxylic acid residues. They exhibit lower selectivity than (137) and consequently are more broad spectrum ionophores. The structure of (138)KI has been solved544 but it was not possible to conclude, with certainty, whether the metal is entrapped in the central cavity, as in related cyclic polyether structures (Figure 14a), or whether it occupi.es a site between two adjacent ligand molecules to give an infinite sandwich (147) as has been found in the RbNCS complex of a synthetic ldlldl isomer of (138).545 Adducts of 1 2 sandwich and 2 3 club sandwich stoichiometry have been proposed for Cs+ complexes of (138),546a and the 1 2 K+ sandwich complex of (138) has been proposed as the species which transports K+ across lipid layers as it shields the metal effectively from solvent interactions.5461 ... 

In 1959 Shchukina et a I. 56 showed that the addition of pyridine to DCC increases the yield (65-85%) of depsipeptides constructed from Z-protected amino acids and serine, threonine, or salicylic acid derivatives. The ferf-butyl ester of Af-(benzyloxycarbonyl)-leucylleucic acid (Table 2) was prepared in 60% yield under the same conditions of addition using a 2 molar excess of pyridine to carbodiimide. 57 The DCC/pyridine technique was successfully utilized in the ring closure between ()-alanine and leucic acid residues during the synthesis of the cyclic hexadepsipeptide destruxin B.[58 Under this modified approach the... 

The polychlorinated cyclic hexadepsipeptides kutznerides 1-9 (1036-1044), which contain both the novel 6.7-d i c h I oroh e x ah yd ropy rro I o 12.3 -/< i n do I e core and several unusual amino acids, are found in the actinomycete Kutzneria sp. 744 inhabiting the roots of Picea abies (1071,1072). These compounds show moderate activity against root-rotting fungi. Another chlorinated he xahydropvitoIo12.37 indole cyclohexapeptide is the dimeric chloptosin (1045) isolated from a Streptomy-... 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

Cyclic lipopeptides containing piperazic acid show potent toxicity against tumor cells. This class of compounds shows potent antibacterial activity against gram-positive bacteria. The following five cyclic lipopeptides are all hexadepsipeptides and are produced by Streptomyces spp. 

Standard procedures were followed for isolation of the toxic principles from mycelium of FA 120. A methylene chloride extract of the freeze-dried hyphae was initially partitioned between hexane and aqueous methanol to separate lipids from more polar material. Bio-assay-monitored chromatographic fractionation of the hexane-soluble material led to the isolation of a fraction (ca. 5% of the hyphal weight) which could account for much of the toxicity of the hyphae of FA 120 to spruce budworm larvae. The spectroscopic and chemical properties of this material were characteristic of the enniatins, a group of cyclic hexadepsipeptide ionophore antibiotics produced by several plant pathogenic Fusarium species, including F. lateritium... 

The association constant for ion binding of Cyclo-(Pro-Gly)3 is nearly the same as that of antamanide, but the selectivity for Ca of Cydo-(Pro-Gly)3 is inferior to that for Na" " of antamanide 144). Cyclo-(Pro-Gly)3 resembles the K -specific cyclic hexadepsipeptide aiitibiotic enniatin 145), in the aspect that both cyclic compounds form sandwich-type comidexes with ions. It is very likely that Cyclo-(Pro y)3 transports ions across a membrane via the formation of a club sandwich-type complex. The metal-ion complex of Cydo-(Proextractable with water from organic phase. A specific behavior of Cyclo Pro-Gly)3 in the ion tran rt throu a membrane is expected from this property. 

Two new hexadepsipeptides, exumolides A and B (143,144), were isolated as white solids from the broth and mycelium of a member of the genus Scytalidium (Hyphomycetes) collected from decaying plant material in the Bahamas. Their structures were elucidated by NMR methods coupled with tandem mass spectrometry (MS-MS) [178]. 

Beauveridn, hexadepsipeptide antibiotic produced by fungi 12MOL2367. Biosynthesis and combinatorial biosynthesis of erythromycin 12CJ01232. Biosynthesis and total synthesis studies on the jadomycin family ofpoly-ketide antibiotics 12EJO2095. 

Kutznerides a-i are antifungal and antimicrobial cyclic hexadepsipeptides isolated from the soil actinomycete Kutzneria sp. 744. These metabolites are... 

Hexadepsipeptides are biosynthesized on a modular NRPS assembly line. Each module performs amino acid activation via adenylation (A) domain-catalyzed acyl-AMP formation, loading the adenylated intermediate to the adjacent T domain, and condensation (C) domain-catalyzed peptide bond formation. 

Enniatin B (Fig. 2B) is a cyclic hexadepsipeptide The ring, which is only half the size of that of valinomycin, is too small to fold into the bracelet conformation of valinomycin and forms a staggered plane The complexing cage is consequently less well defined and the K -.Na selectivity (K Na 3 1) is considerably attenuated... 

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