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PubMed1992

Crystal and molecular structure of the depsipeptide ionophore hexadecaisoleucinomycin, cyclo-[(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24).

The crystal structure of a synthetic depsipeptide ionophore hexadecaisoleucinomycin, cyclo [-(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24), has been determined by single crystal x-ray diffraction techniques. The crystals are orthorhombic, space group P2(1)2(1)2(1), number of molecules per unit cell z = 4, and cell parameters a = 11,195, b = 17.853, c = 54.835 A. The values of the standard (R) and weighted (Rw) discrepancy factors after refinement are 0.122 and 0.135, respectively. The structure is characterized by an elongated bracelet form with a twofold axis of pseudosymmetry. It is stabilized by eight intramolecular 4----1 hydrogen bonds between the amide C = O and N - H groups. The ester carbonyls are directed toward the inside of the molecule, their oxygen atoms forming an ellipsoidal internal cavity. The side chains are located on the molecular periphery. The conformational states of hexadecaisoleucinomycin in solution are discussed in the light of the data obtained.

Amino Acid Sequence↗
PubMed2005

Metal-induced chiral folding of depsipeptide dendrimers.

The synthesis and metal complexation of chiral depsipeptide dendrimers 3 and 7 containing an ethylenediaminetetraacetic acid (EDTA) ester-derived core is reported. The EDTA ester cavity of these dendrimers selectively complexes Zn(2+) and Cu(2+) ions leading to diastereoselective folding. To elucidate the coordination motif in the resulting "foldamers" of 3-ZnCl(2), 7-ZnCl(2), 3-CuCl(2), and 7-CuCl(2), the coordination behavior of the tetramethyl ester of EDTA (8) has been investigated as a model case. The corresponding complexes 8-ZnCl(2) and 8-CuCl(2) have been structurally characterized by (1)H NMR spectroscopy and X-ray analysis. The complexes involve the inherently chiral octahedral cis-alpha coordination motif, in which 8 serves as a tetradentate ligand. In the case of the Zn(II) complex 8-ZnCl(2), both Deltacis-alpha(S,S,lambda) and Lambdacis-alpha(R,R,lambda) stereoisomers were found in the unit cell. For the Cu(II) complex 8-CuCl(2), only one stereoisomer, namely Deltacis-alpha(S,S,lambda) was found in the crystal under investigation. (1)H NMR spectroscopy has shown that the same coordination motif is diastereoselectively formed in the chiral Zn(2+) dendrimers 3-ZnCl(2) and 7-ZnCl(2). Likewise, the calculated CD spectrum of the Deltacis-alpha(S,S,lambda) stereoisomer of the model complex 8-CuCl(2) shows good agreement with the experimental spectrum of the Cu(II) dendrimers 3-CuCl(2) and 7-CuCl(2), allowing assignment of the absolute configurations of the preferred foldamers as Lambdacis-alpha(R,R,lambda) for 3-CuCl(2) and Deltacis-alpha(S,S,lambda) for 7-CuCl(2). This work represents the first example of metal-complexation-mediated diastereoselective folding of chiral dendrimers with known absolute configuration.

Circular Dichroism↗
PubMed2003

The cyclization of peptides and depsipeptides.

Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

Amino Acid Sequence↗
PubMed1996

Synthetic depsipeptide substrates for the assay of human hepatitis C virus protease.

Hepatitis C virus (HCV) is the major etiological agent of both parenterally transmitted and sporadic non-A, non-B hepatitis. The disease is a major health problem with an estimated 50 million people infected worldwide, a high percentage of whom become chronically infected and are at high risk for liver cirrhosis. The serine protease contained within the N-terminal region of the nonstructural protein 3 (NS3 protease) of HCV is considered a promising target for the development of an antiviral therapy. A prime requisite to study in detail the biochemistry of the protease as well as develop inhibitors is the availability of a fast and sensitive in vitro assay of enzyme activity. However, due to their low kcat/Km values, synthetic peptide substrates based on the natural cleavage sites appear unsuitable for this purpose. We show here that appropriate substrates can be obtained by substituting the scissile amide bond with an ester linkage. The resulting depsipeptides show >100-fold improvement in kcat/Km values, up to 13,000 M-1 s-1, enabling detection of activity with subnanomolar NS3 concentrations. The ester substrates are obtained in high yield entirely by solid-phase synthesis using commercially available materials, without the need for any preassembled building blocks.(c) 1996 Academic Press, Inc.

Amino Acid Sequence↗
PubMed1995

Korkormicins, novel depsipeptide antitumor antibiotics from Micromonospora sp C39500: fermentation, precursor directed biosynthesis and biological activities.

Micromonospora sp C39500, isolated in our laboratory from a soil sample, produced a complex of seven novel depsipeptide antitumor antibiotics, designated korkormicins. The major component of the complex, korkormicin A, has a MW of 1452 and a molecular formula of C66H84N16O22. Korkormicin A exhibits potent in vivo antitumor activity against P388 leukemia and M109 lung carcinoma implanted intraperitoneally (ip) in mice, with effective doses of 0.05-0.20 mg kg-1 injection-1, for five or three ip injections, respectively. It is also active against Gram-positive bacteria but inactive against Gram-negative bacteria. The production of korkormicin A was enhanced by 3-fold when 0.1% L-valine was added to the production culture at 48 h. A titer of 401.0 micrograms ml-1 was achieved in the fermenter culture supplemented with 0.1% L-valine.

Animals↗
PubMed2001

Activity of the cyclic depsipeptide emodepside (BAY 44-4400) against larval and adult stages of nematodes in rodents and the influence on worm survival.

The present investigations deal with the activity of the cyclic depsipeptide emodepside (BAY 44-4400) against larval and adult stages of three rodent nematodes. While emodepside acts strongly against the adult stages of the rat nematodes Nippostrongylus brasiliensis and Strongyloides ratti, as well as against the mouse nematode Heligmosomoides polygyrus, its actions against the larval stages of these nematodes vary according to the species. Thus, emodepside is highly effective against the lung and intestine larval stages of N. brasiliensis and S. ratti. By contrast. the larval stages of H. polygyrus in the intestine are only partly affected by higher emodepside dosages.

Animals↗
PubMed1989

Preparative reversed-phase high-performance liquid chromatography in the synthesis of viscosin, a cyclic depsipeptide.

The importance of peptides in biochemical research and the facility with which they can be prepared by solid-phase techniques highlights the need for continuing research in the chromatographic purification of these molecules on a preparative scale. In this regard, synthesis of the cyclic depsipeptide antibiotic, viscosin, has provided the opportunity to demonstrate the use of radial compression cartridge technology in the reversed-phase purification of three key peptide intermediates on a scale of several hundred milligrams. Superior resolution of linear and cyclic peptide mixtures on a Bondapak C18 radial compression cartridge by using an aqueous acetonitrile solvent system containing 0.1% trifluoroacetic acid contributed significantly to the first total synthesis of viscosin, and demonstrates the applicability of this system to the purification of peptide mixtures.

Amino Acid Sequence↗
PubMed2002

Antibody-catalyzed cleavage of the D-Ala-D-Lac depsipeptide: an immunological approach to the problem of vancomycin resistance.

Vancomycin resistance is currently a major healthcare problem. The development of a catalytic monoclonal antibody (mAb) that hydrolyzes the D-Ala-D-Lac depsipeptide provides a potentially novel antibiotic strategy. A phosphonate hapten design was used to program antibody catalysis. The characteristics of the hapten were shown to be important for obtaining a viable immune response and several catalytic mAbs that cleave a peptidoglycan model substrate. The best mAb afforded a >500-fold rate enhancement over background.

Animals↗
PubMed1999

A "cephalosporin-like" cyclic depsipeptide: synthesis and reaction with beta-lactam-recognizing enzymes.

The cyclic depsipeptide 8-carboxy-3-phenylacetamido-3,4-dihydro-2H-1-benzopyran-2-one, a cyclic analog of aryl phenaceturates with structural similarity to cephalosporins, has been synthesized as a potential substrate/inhibitor of B-lactam-recognizing enzymes. It was found to be a tight-binding, poor substrate of class A beta-lactamases and an irreversible inhibitor of several DD-peptidases.

Carboxypeptidases↗
PubMed1994

Functionalized depsipeptides, substrates and inhibitors of beta-lactamases and DD-peptidases.

A series of derivatives of phenyl phenylacetylglycinates (aryl phenaceturates) with a carboxylate substituent meta to the oxygen of the phenoxide leaving group and a functionalized methylene group in the ortho- or para-position have been synthesized. These molecules possess a latent o- or p-quinone methide electrophile which could be unmasked during enzymic turnover and could react with an active site nucleophile. This chemistry does seem to occur in solution where a common hydrolysis product, independent of the benzylic leaving group, presumably o- or p-hydroxymethylphenol, was observed. These depsipeptides are substrates of class A and C beta-lactamases, particularly of the latter, comparable with the parent m-carboxyphenyl phenaceturate. They also have modest inhibitory activity against these enzymes and against the serine DD-peptidase of Streptomyces R61. The inhibition of a class C beta-lactamase was turnover dependent, as expected of mechanism-based inhibitor, but the small leaving group dependence of the inhibition suggested that the quinone methide, if it was in fact responsible for the inhibition, was generated in solution subsequent to release of the product phenol from the active site.

Anti-Bacterial Agents↗
PubMed1986

Activity of copper-substituted carboxypeptidase A toward oligopeptides and depsipeptides.

Cu(II)-substituted carboxypeptidase A catalyzes the hydrolysis of oligopeptides and their depsipeptide (ester) analogues. Stopped-flow fluorescence assays demonstrate that relative to the zinc enzyme the Cu enzyme can have kcat/Km values up to 24% toward esters but only up to 2.5% toward the corresponding peptides. Adding Zn(II) to the copper enzyme reveals a slow exchange process that correlates with an increase in peptidase activity and with changes in the Cu(II) electron paramagnetic resonance spectra. Low concentrations of 1,10-phenanthroline (OP) (0.1-2.5 microM) markedly increase activity toward furanacryloyl-Phe-Phe (up to 8% of the zinc enzyme), but higher concentrations inhibit, resulting in complete inhibition at 0.8 mM OP. The non-metal-binding, hydrophobic analogues m- and p-phenanthroline are only activators of peptide hydrolysis, even at 1 mM. Activation is likely due to a modifier binding to a hydrophobic locus and either displacing an inhibitory peptide binding mode or inducing a conformational change in the active site.

Carboxypeptidases↗
PubMed1989

Beta-lactamase-catalyzed aminolysis of depsipeptides: amine specificity and steady-state kinetics.

beta-Lactamases catalyze not only the hydrolysis but also the aminolysis of certain depsipeptides [Pratt, R. F., & Govardhan, C. P. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1302-1306]. This paper explores further the specificity of the aminolysis reaction with respect to the structure of the amine and also the steady-state kinetics of the reaction. The amines preferred by the class C beta-lactamase of Enterobacter cloacae P99 appear to be aromatic D-alpha-amino acids. The general order of substrate effectiveness at pH 7.5 appears to be aromatic D-alpha-amino acids greater than large aliphatic D-alpha-amino acids greater than small aliphatic D-alpha-amino acids approximately small aliphatic L-alpha-amino acids greater than large L-alpha-amino acids. Charges on the aliphatic side chains seem unimportant. Ineffective as acyl acceptors were beta-amino acids, alpha-amino phosphonic acids, and, in general, amines, including amino acid carboxyl derivatives and peptides. There is thus strong evidence for specific interaction between the amine and the enzyme. A detailed kinetics study was made of the P99 beta-lactamase-catalyzed aminolysis of m-[[(phenylacetyl)glycyl]oxy]benzoic acid by D-phenylalanine. The steady-state kinetics were complex because of the presence of parallel enzyme-catalyzed hydrolysis and aminolysis reactions. An empirical rate equation was obtained for the total reaction. This has important elements in common with that previously found for the aminolysis of specific peptides by the DD-peptidases of various Streptomyces strains [e.g., Frere, J.-M., Ghuysen, J.-M., Perkins, H.R., & Nieto, M. (1973) Biochem. J. 135, 483-492].(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1989

Beta-lactamase-catalyzed aminolysis of depsipeptides: peptide inhibition and a new kinetic mechanism.

The aminolysis of the depsipeptide m-[[(phenylacetyl)glycyl]oxy]benzoic acid (1) by D-phenylalanine, catalyzed by the beta-lactamase of Enterobacter cloacae P99, is inhibited by the product of the reaction, (phenylacetyl)glycyl-D-phenylalanine (2), by the peptide analogue of 1, m-[(phenylacetyl)-glycinamido]benzoic acid (3), and by (3-dansylamidophenyl)boronic acid. Analysis of the steady-state kinetics of the effect of 2 and 3 on the reaction indicated that both a competitive binding mode and a noncompetitive binding mode existed for each peptide. Thus, there probably are two distinct binding sites (sites 1 and 2) that 2 and 3, and by implication 1, are able to simultaneously occupy on the enzyme surface. Given this information, it was possible to devise a new kinetic mechanism for the aminolysis reaction which yielded the experimentally observed empirical rate equation [Pazhanisamy, S., Govardhan, C. P., & Pratt, R. F. (1989) Biochemistry (first of three papers in this issue)] but did not involve initial binding of D-phenylalanine to the free enzyme, which has been shown not to occur [Pazhanisamy, S., & Pratt, R. F. (1989) Biochemistry (second of three papers in this issue)]. The mechanism requires two different 1:1 enzyme/1 complexes, only one of which leads to the hydrolysis and aminolysis reactions (1 in site 1), and a 1:2 enzyme/1 complex (1 in both sites), which leads only to hydrolysis. The dansyl boronate inhibits by binding competitively with 1 in site 1. It is suggested that this scheme also applies to the analogous transpeptidase reactions of small model peptides catalyzed by the bacterial cell wall DD-peptidases, where similar steady-state kinetics have been observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMedDate not supplied

Solid phase library synthesis of cyclic depsipeptides: aurilide and aurilide analogues.

A solid-phase combinatorial synthesis approach toward the cyclic depsipeptide aurilide (1) and related analogues is described. The peptide moiety 2 was assembled on trityl linker-functionalized SynPhase Crowns using an Fmoc strategy. Optimization of the tetrapeptide assembly 5 was carried out using parallel multiple synthesis and LC/MS analysis. The aliphatic moiety 3a was coupled with the solid-supported 2 using DIC/HOBt. Following deprotection and cleavage of linear precursor 26, macrocyclization was achieved under high dilution conditions. Removal of the methylthiomethyl protecting group provided aurilide (1) in 11% overall yield. Synthesis of a combinatorial library of aurilide derivatives 4 was accomplished with a similar protocol using the TranSort technique.

Anti-Bacterial Agents↗
PubMed1999

Synthesis and Reactivity with beta-Lactamases of "Penicillin-like" Cyclic Depsipeptides.

Several 7-carboxy-3-amido-3,4-dihydro-2H-1-benzopyran-2-ones have been synthesized as potential beta-lactamase substrates and/or mechanism-based inhibitors. Substituted o-tyrosine precursors were prepared by the Sörensen method and then heated in vacuo to give the lactones. These compounds are cyclic analogues of aryl phenaceturates which are known to be beta-lactamase substrates. The goal of incorporating the scissile ester group into a lactone was to retain the leaving group tethered to the acyl moiety at the acyl-enzyme stage of turnover by serine beta-lactamases, in a manner similar to that during penicillin turnover. Further, in two cases, a functionalized methylene group para to the leaving group phenoxide oxygen was incorporated. These molecules possess a latent p-quinone methide electrophile which could, in principle, be unmasked during enzymic turnover and react with an active site nucleophile. All of these compounds were found to be substrates of class A and C beta-lactamases, the first delta-lactones with such activity. Generally, k(cat) values were smaller than for the analogous acyclic depsipeptides, which suggests that the tethered leaving group may obstruct the attack of water on the acyl-enzymes. Further exploration of this structural theme might lead to quite inert acyl-enzymes and thus to significant inhibitors. Despite the apparent advantage offered by the longer-lived acyl-enzymes, the functionalized compounds were no better as irreversible inhibitors than comparable acyclic compounds [Cabaret, D.; Liu, J.; Wakselman, M.; Pratt, R. F.; Xu, Y. Bioorg. Med. Chem. 1994, 2, 757-771]. Thus, even tethered quinone methides, at least when placed as dictated by the structures of the present compounds, were unable to efficiently trap a nucleophile at serine beta-lactamase active sites.

Journal Article↗
PubMed1999

Polyoxypeptins A and B Produced by Streptomyces: Apoptosis-Inducing Cyclic Depsipeptides Containing the Novel Amino Acid (2S,3R)-3-Hydroxy-3-methylproline.

Potent apoptosis-inducing peptides, polyoxypeptins A (1) and B (2) were isolated from the culture broth of Streptomyces sp. by solvent extraction and column chromatography. Structural elucidation of 1 by MS and NMR analyses revealed that it is a cyclic hexadepsipeptide having a novel amino acid and a previously unrecognized N-acyl side chain. The depsipeptide consisted of 3-hydroxyleucine, N-hydroxyvaline, N-hydroxyalanine, piperazic acid, 5-hydroxyhexahydropiperazine-3-carboxylic acid, and an unusual and hitherto unreported amino acid, 3-hydroxy-3-methylproline. Alanine and valine obtained from the hydrolyzate of 1 were both in the L-configuration as concluded from chiral TLC analysis. Then, the absolute structure of 1 was determined with the relative structure obtained from X-ray crystallographic analysis, and the new amino acid was isolated and confirmed to be (2S,3R)-3-hydroxy-3-methylproline (3). MS and NMR of 2 exhibited that it is a monodeoxy compound of 1. Stereochemistry of 2 was determined by degradation studies. Both 1 and 2 at a concentration of about 0.1 &mgr;g/mL induced early cell death, nuclear fragmentation, and internucleosomal DNA scission, all of which are characteristic of apoptosis, in human pancreatic carcinoma AsPC-1 cells.

Journal Article↗