Hydroxy Acid Residues Research Articles

Stereoselective Synthesis of a Protected Side Chain of Callipeltin A.

Matteson homologations of chiral boronic esters proved to be an excellent tool for the synthesis of highly functionalized amino and hydroxy acid residues. This method provides straightforward stereoselective access to the side chain of callipeltin A, a natural marine product with interesting biological activities. Furthermore, this protocol should allow for variations in the substitution pattern in future SAR studies, simply by choosing suitable nucleophiles during the homologation steps.

Structural basis of keto acid utilization in nonribosomal depsipeptide synthesis.

Nonribosomal depsipeptides are natural products composed of amino and hydroxy acid residues. The hydroxy acid residues often derive from α-keto acids, reduced by ketoreductase domains in the depsipeptide synthetases. Biochemistry and structures reveal the mechanism of discrimination for α-keto acids and a remarkable architecture: flanking intact adenylation and ketoreductase domains are sequences separated by >1,100 residues that form a split 'pseudoAsub' domain, structurally important for the depsipeptide module's synthetic cycle.

A Possible Path to Prebiotic Peptides Involving Silica and Hydroxy Acid-Mediated Amide Bond Formation.

The formation of alanine and glycine oligomers in films produced by drying aqueous mixtures of lactic acid and silica nanoparticles has been studied as a model prebiotic reaction. The addition of silica results in alanine or glycine enrichment in the polymers. Oligomerization proceeds through ester-mediated peptide bond formation in an acidic and evaporative environment at temperatures as low as 85 °C. For both amino acids, the dominant species produced in the presence of silica and lactic acid are rich in amide bonds and deficient in ester linkages. At higher temperatures, glycine and alanine oligomers contain only a single hydroxy acid residue conjugated to the peptide N terminus. Similar product distributions occur with silica particles prereacted with lactic acid, which suggests the catalytic role of a functionalized surface. This work highlights the role minerals might have served in transitioning from oligomers with both ester and amide linkages (depsipeptides) to peptides in a prebiotic context.

Chemical Classification of Cyclic Depsipeptides

Cyclic depsipeptides (CDPs) are a family of cyclic peptide-related compounds, of which the ring is mainly composed of amino- and hydroxy acid residues joined by amide and ester bonds (at least one), leading to a wide diversity of fascinating chemical structures. They differ in both their ring structure and their side chains, especially by the nature of the unusual and non-amino acid building blocks. To date, however, there is no overall uniform chemical classification system available for CDPs and naming of the diverse family members is done rather arbitrarily. Therefore, a broad evaluation of different CDP structures is done, i.e., 1348 naturally occurring CDPs were included, and a straightforward chemical classification system using apparent chemical characteristics is proposed in order to organize the currently scattered CDP data. The overall validity of the classification approach is verified and the compounds categorized in the same groups are considered to be structurally related. This evaluation also revealed that traditionally formed CDP subfamilies, like the dolastatins, might be misleading from a chemical point of view given the structural differences in this subfamily. This up-to-date CDP overview enables peptide and natural product scientists to study the wide diversity in CDP structures, their chemical interrelationships and identification of existing and newly found CDPs. Together with the available information on the species producing these CDPs and their reported biological activities, this paper provides a useful tool to gain new insights into this diverse group of peptides.

Antiplasmodial and antiviral cyclohexadepsipeptides from the endophytic fungus Pullularia sp. BCC 8613

Four new cyclohexadepsipeptides, pullularins A–D, were isolated from the endophytic fungus Pullularia sp. BCC 8613. Structures of these compounds were elucidated by interpretation of NMR spectroscopic and mass spectrometric data. The absolute configurations of amino acid and hydroxy acid residues were determined by HPLC analysis of depsipeptide acid hydrolyzates using a chiral column and Marfey's method. Pullularin A exhibited activities against the malarial parasite Plasmodium falciparum K1 (IC 50 3.6 μg/mL) and herpes simplex virus type 1 (HSV-1; IC 50 3.3 μg/mL), whereas it showed weak cytotoxicity to Vero cells (IC 50 36 μg/mL).

Paecilodepsipeptide A, an Antimalarial and Antitumor Cyclohexadepsipeptide from the Insect Pathogenic Fungus Paecilomyces cinnamomeus BCC 9616

Paecilodepsipeptide A (1), a new cyclohexadepsipeptide possessing three d-amino acid residues, together with its linear analogues paecilodepsipeptides B (2) and C (3), was isolated from the insect pathogenic fungus Paecilomyces cinnamomeus BCC 9616. Structures of these compounds were elucidated primarily by NMR and mass spectroscopic analyses. The absolute configurations of the amino acid and hydroxy acid residues of 1 were addressed by HPLC analysis of its acid hydrolyzate using a chiral column and Marfey's method. Paecilodepsipeptide A (1) showed activity against the malarial parasite Plasmodium falciparum K1 with an IC50 value of 4.9 microM. This compound also showed cytotoxicity to two cancer cell lines, KB (IC50 5.9 microM) and BC (IC50 6.6 microM); however, it was inactive against noncancerous Vero cells up to 67 microM (50 microg/mL).

Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides.

Amyloid deposits are formed as a result of uncontrolled aggregation of (poly)peptides or proteins. Today several diseases are known, for example Alzheimer's disease, Creutzfeldt-Jakob disease, mad cow disease, in which amyloid formation is involved. Amyloid fibrils are large aggregates of beta-pleated sheets and here a general method is described to introduce molecular mutations in order to achieve disruption of beta-sheet formation. Eight backbone-modified amylin derivatives, an amyloidogenic peptide involved in maturity onset diabetes, were synthesized. Their beta-sheet forming properties were studied by IR spectroscopy and electron microscopy. Modification of a crucial amide NH by an alkyl chain led to a complete loss of the beta-sheet forming capacity of amylin. The resulting molecular mutated amylin derivative could be used to break the beta-sheet thus retarding beta-sheet formation of unmodified amylin. Moreover, it was found that the replacement of this amide bond by an ester moiety suppressed fibrillogenesis significantly. Introduction of N-alkylated amino acids and/or ester functionalities-leading to depsipeptides-into amyloidogenic peptides opens new avenues towards novel peptidic beta-sheet breakers for inhibition of beta-amyloid aggregation.

Crystal structure of a depsipeptide, Boc-(Leu-Leu-Lac)3-Leu-Leu-OEt.

A sequential polydepsipeptide, Boc-(Leu-Leu-Lac)3-Leu-Leu-OEt (1) (Lac = L-lactic acid residue) has been synthesized by the segment condensation method. The sequential unit of 1, -Leu-Leu-Lac-, is consisted of two amino acid residues and one hydroxy acid residue. X-ray diffraction measurement with an imaging plate detector and a direct-methods procedure of Shake-and-Bake successfully revealed the crystal structure of 1. In the solid state, the 11-mer depsipeptide, 1, have clear alpha-helical conformation even with the three ester linkages.

Destruxin analogs: variations of the alpha-hydroxy acid side chain.

This work describes the synthesis of three destruxin E cyclodepsipeptidic analogs. These compounds have an identical amino acid sequence but differ by the nature of the hydroxy acid residue with is 2-hydroxy-3-phenylpropionic (Hpp), 2-hydroxy-5-trimethylsilyl-4-pentynoic (Hpy-TMS) and 2-hydroxy-4-pentynoic (Hpy) acid, respectively. The insecticidal properties on the Galleria mellonella larvae (paralysis and lethal effect) of these analogs are presented in comparison with the natural destruxin E. All these compounds have toxic effects, the most potent being Hpy that induces the same effect as destruxin E.

Cyclodepsipeptides from Beauveria bassiana. Part 3. The isolation of beauverolides Ba, Ca, Ja, and Ka

Beauverolides Ja and Ka are shown to be the cyclotetradepsipeptides cyclo-[3-hydroxy-4-methyloctanoyl-L-tryptophyl-L-phenylalanyl-D-alloisoleucyl] and the 3-hydroxy-4-methyldecanoyl homologue, respectively. Pairs of beauverolides differing only in the hydroxy-acid residue are readily separated by high-pressure liquid chromatography and beauverolides Ba and Ca have been isolated using this technique.

Nonbonded interactions in membrane‐active cyclic biopolymers. III. Analogs of valinomycin

AbstractSeveral analogs of valinomycin have been simulated. These are analogs obtained by changing the configuration of the amino acid and hydroxy acid residues one at a time. Nonbonded interactions have been calculated for three conformations of each analog. The electrostatic and polarization contributions to the energy are conformation selective, whereas the Pauli repulsion is the only component which is isomer selective. For the ring chirality considered here the analog of valinomycin having all the three L‐valyl residues replaced by D‐valyl residues is predicted to be frozen in a “top open” conformation.

Refinement of the solution conformation of valinomycin with the acid coupling constants from the 13C-nuclear-magnetic-resonance spectra.

The C′= O and Cα signals in the 13C nuclear magnetic resonance (NMR) spectra of valinomycin have been assigned and the vicinal 1H…13C coupling constants have been determined by double and triple heteronuclear resonance. In conjunction with the vicinal H-NCα-H and H-CαCβ-H proton-proton constants, the results led to unequivocal determination of the torsion angles φ and of the population distribution of the Cα-Cβ rotational states. The Φ torsion angles for the hydroxy acid residues were estimated from the vicinal 1H-CαC′-15N constants. The combined data permitted refinement of the conformational states of valinomycin in different solvents. For the KS+ complex of valinomycin the observed couplings are in complete accord with the conformations we had earlier proposed for solutions and that had also been established by X-ray analysis. In the 13C spectra of the valinomycin-Tl+ complex 13C…203,205Tl+ spin-spin couplings were observed for the l and d-valine carbonyls, unequivocal proof of the donor-acceptor interaction with the cation. In media of weak polarity (cyclohexane, chloroform) the conformation of the valinomycin molecule is similar to that of the K+ complex. In such a ‘bracelet’ structure formed by six fused β-turns of type II and II′, the amino acid carbonyls are axial with certain inclination towards the symmetry axis. On formation of a 1:1 complex with a cation the carbonyl orientation changes, now bending towards the center of the molecular cavity. In the ‘propeller’ conformation, predominant in solvents of medium polarity (for instance CCl4/(C2H3)2SO, 3/1) the three β-turns are of type II. The 1H and 13C chemical shifts are interpreted in terms of conformational changes in the valinomycin molecule, intermolecular and intramolecular hydrogen bonds and interaction with the metal cation.

Synthesis of new analogs of valinomycin and their properties. I

1. The synthesis of five valinomycin analogs differing by the configurations of the amino-acid and hydroxy-acid residues and also by the volumes of the radicals of the hydroxy-acid residues has been effected.

Isolation and structure of mycobactin T, a growth factor from Mycobacterium tuberculosis

1. A growth factor for Mycobacterium johnei has been isolated from Mycobacterium tuberculosis as an iron complex; it has been named ferric mycobactin T. 2. Ferric mycobactin T as isolated is a mixture of at least four closely related components differing only in their fatty acid side chains. 3. Mycobactin T resembles mycobactin P in structure but differs in the following respects: (a) the aromatic acid residue is salicylic acid in place of 2-hydroxy-6-methylbenzoic acid; (b) the hydroxy acid residue is (+)-beta-hydroxybutyric acid in place of (-)-3-hydroxy-2-methylpentanoic acid; (c) its components have fatty acid side chains that are mostly different from the side chains of the components in mycobactin P preparations. One minor component in mycobactin T has probably a cis-octadec-2-enoyl side chain. The major side-chain components correspond to acids of chain length C(18)-C(21) that are not n-saturated or n-Delta(2)-unsaturated acids. 4. The differences in biosynthesis between mycobactins T and P are discussed.

Studies in the field of depsipeptides LI. Mass-spectrometric study of cyclotetradepsipeptides of regular structure

1. The mass-spectrometric behavior of various cyclotetradepsipeptides of regular structure has shown that the CO2 type of fragmentation is most characteristic for them. 2. The results of the present investigation, with the regular features of the mass-spectrometric behavior of other types of cyclic depsipeptides [1] taken into account, permits an adequate amount of information to be obtained from the mass spectra for deciding a number of questions of structure and analysis: the determination of the size of the ring, the regularity of the structure, the symmetry with respect to aminoacid and hydroxyacid residues, and also the nature of these residues.