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PubMed1999

Bioanalysis of aplidine, a new marine antitumoral depsipeptide, in plasma by high-performance liquid chromatography after derivatization with trans-4-hydrazino-2-stilbazole.

A sensitive bio-analytical assay in plasma of the depsipeptide aplidine is reported, based on reversed-phase liquid chromatography and fluorescence detection of the trans-4'-hydrazino-2-stilbazole (4'H2S) derivative of the analyte. At ambient temperature, two conformations of the depsipeptide are observed in solution due to cis-trans isomerism at the proline-pyruvoyl peptide bond. Aplidine is isolated from the matrix by solid-phase extraction on an octadecyl modified silica stationary phase. After evaporation of the acetone eluate, a derivatization with 4'H2S is performed in a water-acetonitrile mixture at pH 4. The reaction mixture is injected directly into the chromatograph and the analyte is quantified by fluorescence detection at 410 and 560 nm for excitation and emission, respectively. The method has been validated in the 2-100 ng/ml-range, 2 ng/ml being the lower limit of quantification. Precision and accuracy both meet the current requirements for a bioanalytical assay. The identity of the 4'H2S reaction products of aplidine have been confirmed by mass spectrometric analysis. Finally, the method has been employed for a pilot pharmacokinetic study of aplidine in mice which demonstrated its usefulness for pharmacological research.

Animals↗
PubMed2005

The wewakpeptins, cyclic depsipeptides from a Papua New Guinea collection of the marine cyanobacterium Lyngbya semiplena.

Four new depsipeptides have been isolated from the marine cyanobacterium Lyngbya semiplena collected from Papua New Guinea. The amino and hydroxy acid partial structures of wewakpeptins A-D (1-4) were elucidated through extensive spectroscopic techniques, including HR-FABMS, 1D (1)H and (13)C NMR, as well as 2D COSY, HSQC, HSQC-TOCSY, and HMBC spectra. The sequence of the residues was determined through a combination of multifaceted approaches including ESI-MS/MS, HMBC, ROESY, and a modified 1D HMBC experiment. The absolute stereochemistry of each residue was determined by chiral HPLC and chiral GC-MS methods. The wewakpeptins represent an unusual arrangement of amino and hydroxy acid subunits relative to known cyanobacterial peptides and possess a bis-ester, a 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya) or 2,2-dimethyl-3-hydroxyoctanoic acid (Dhoaa) residue, and a diprolyl group reminiscent of dolastatin 15. Wewakpeptin A and B were the most cytotoxic among these four depsipeptides with an LC(50) of approximately 0.4 muM to both the NCI-H460 human lung tumor and the neuro-2a mouse neuroblastoma cell lines.

Amino Acid Sequence↗
PubMed2002

Phoriospongin A and B: two new nematocidal depsipeptides from the Australian marine sponges Phoriospongia sp. and Callyspongia bilamellata.

Bioassay-directed fractionation of two southern Australian sponges, Phoriospongia sp. and Callyspongia bilamellata, yielded two new nematocidal depsipeptides, identified as phoriospongins A (1) and B (2). The structures of the phoriospongins were determined by detailed spectroscopic analysis and comparison with the previously reported sponge depsipeptide cyclolithistide A (3), as well as ESIMS and HPLC analysis of acid hydrolysates. It is noteworthy that the unique and yet structurally related metabolites 1-3 are found in sponges spanning three taxonomic orders, Poescilosclerida, Haplosclerida, and Lithistida.

Amino Acids↗
PubMed2003

Isolation of homodolastatin 16, a new cyclic depsipeptide from a Kenyan collection of Lyngbya majuscula.

An examination of an organic extract of the cyanobacterium Lyngbya majuscula, collected from Wasini Island off the southern Kenyan coast, led to the isolation of the known cyclic depsipeptide antanapeptin A (1), recently isolated from a Madagascan collection of L. majuscula, and a new bioactive cyclic depsipeptide, homodolastatin 16 (2). The structures of these two compounds were determined from NMR and mass spectrometry data. Homodolastatin 16, a higher homologue of the potential anticancer agent dolastatin 16, exhibited moderate activity against oesophageal and cervical cancer cell lines.

Antineoplastic Agents↗
PubMed2005

A new strategy for solid-phase depsipeptide synthesis using recoverable building blocks.

The technique of choice for synthesis of small-scale depsipeptides is on a solid support. However, if expensive monomers have to be incorporated, solid-phase synthesis can quickly turn out to be unattractive because of its low atom economy. Herein, we describe a new type of recoverable and reuseable alpha-hydroxy acid building block for solid-phase synthesis and its application in the synthesis of a number of small cyclic depsipeptides. [structure: see text]

Amino Acids↗
PubMed1999

Unique molecular conformation of aureobasidin A, a highly amide N-methylated cyclic depsipeptide with potent antifungal activity: X-ray crystal structure and molecular modeling studies.

A structural feature of aureobasidins, cyclic depsipeptide antibiotics produced by Aureobasidium pullulans R106, is the N-methylation of four out of seven amide bonds. In order to investigate possible relationship between the molecular conformation and the amide N-methylation, aureobasidin A (AbA), which exhibits the potent antifungal activity, was subjected to X-ray crystal analysis. The crystal, recrystallized from ether (orthorhombic, space group P2(1)2(1)2(1), a = 21.643 (3) A, b = 49.865(10) A, c = 12.427 (1) A, z= 8), contained two independent conformers per asymmetric unit and they took on a similar arrowhead-like conformation. The conformation consisted of three secondary structures of antiparallel beta-sheet, and beta- and gamma-turns, and was stabilized by three intramolecular and transannular N-H O=C hydrogen bonds. The beta-hydroxy-N-methyl-l-valine residue, which is indispensable for its bioactivity, was located at the tip of the corner. Since a nearly identical conformation has been observed for aureobasidin E, a related cyclic depsipeptide, this arrowhead-like conformation may be energetically stable and important for biological activity. The contribution of the amide N-methylation to the conformation was investigated by model building and energy calculations. The energy-minimizations of AbA analogs, in which some (one to four) of four N-methylated amide bonds were replaced with usual amide bond, led to some conformers which are fairly different from the arrowhead form of AbA, although they are stabilized by three intramolecular N-H...O=C hydrogen bonds. This result explains the reason why four out of the seven amide bonds have to be methylated to manifest biological activity, i.e. the high N-methylation of aureobasidin is necessary to form only one well-defined conformation.

Antifungal Agents↗
PubMed1988

Crystal and molecular structure of didemnin B, an antiviral and cytotoxic depsipeptide.

Didemnin B, a highly active depsipeptide isolated from a Caribbean tunicate, crystallizes from chloroform/benzene in the orthorhombic space group C2221, with cell parameters a = 14.990 +/- 0.003 A, b = 22.574 +/- 0.004 A, c = 41.112 +/- 0.009 A, V = 13911.7 A3 at 138 K and a calculated density of 1.143 g/cm3 based on C57H89N7O15, 1.5C6H6.H2O and eight formula units per cell. The overall agreement factor R = 0.052 for 7699 reflections, 20 theta max = 150 degrees, Cu K-alpha radiation. The structure determination revealed that didemnin B contains an isostatine residue instead of a statine residue. The conformation of the 23-membered depsipeptide ring is stabilized by one transannular hydrogen bond. The ring does not show the antiparallel beta-pleated-sheet structure but, instead, has a fold in the shape of a bent figure-eight. The linear peptide moiety, containing N-methylleucine and lactylproline, forms a beta (II)-bend and is folded back toward the cyclic backbone, giving the overall molecule a globular character. Comparison with the structure of cyclosporin A shows distinct stereochemical differences between the two molecules. It is suggested that didemnin B and cyclosporin A are unlikely to have a common receptor binding site.

Antiviral Agents↗
PubMedDate not supplied

Crystal and molecular structure of didemnin A, an antiviral depsipeptide.

The molecular structure of didemnin A, the parent compound of a series of antiviral cytotoxic depsipeptides extracted from a marine tunicate Trididemnum solidum of the family of Didemnidae, has been determined by single-crystal X-ray diffraction. In the crystal, didemnin A molecules form pseudo-symmetric dimeric pair. The two molecules in the dimer are held together by strong N--H center dot center dot center dot O and N--H center dot center dot center dot N hydrogen bonds. A chloride ion, placed almost symmetrically between the dimeric pair, forms N--H center dot center dot center dot Cl hydrogen bonds (3.19 and 3.23 Angstrom) with both the molecules. The two independent molecules in the structure have closely similar geometry. For each molecule, the 23-membered depsipeptide ring assumes a folded conformation in the shape of a 'bent figure-of-eight' similar to that observed in the didemnin B crystal structure. The major conformational differences in the macrocycle of didemnin A and didemnin B are around the Hip residue. The root mean-square (RMS) difference of 20 of the 23 endocyclic torsion angles for the two structures is less than 10 degrees, while the three bond torsions in the Hip residue vary by about 50 degrees. The macrocycle conformation is stabilized by a transannular N--H center dot center dot center dot O hydrogen bond linking the isostatine amide group with the leucine carbonyl group. The truncated linear chain is folded back toward the macrocyclic ring and is held by a N--H center dot center dot center dot O hydrogen bond between the leucine amide group and Me-Leu carbonyl group. The transannular hydrogen bond in the didemnin A structure (N4--H center dot center dot center dot O3 = 2.83 Angstrom in both molecule a and molecule b) is noticeably stronger than that observed in the didemnin B structure (3.02 Angstrom). The X-ray structure of didemnin A is generally consistent with that obtained by NMR studies. Within the crystal, the molecules are packed in zig-zag chains formed by intermolecular O--H center dot center dot center dot O hydrogen bonds. The crystal structure and packing of didemnin A are quite different from that of the didemnin B structure.

Antiviral Agents↗
PubMed2005

Controlling production of brominated cyclic depsipeptides by Pseudoalteromonas maricaloris KMM 636T.

AIMS: This study aims at evaluating the impact of the nutrient medium components on the in vitro production of the cytotoxic alterochromides. METHODS AND RESULTS: The employment matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) facilitated the identification of a range of brominated cyclic depsipeptides with molecular masses of 843/845, 857/859 and 922/924/926 Da, and 936/938/940 Da produced by the marine bacterium Pseudoalteromonas maricaloris KMM 636T. The fractions of cytotoxic yellow pigments yielded after methanol extraction of P. maricaloris KMM 636T cells grown on five nutrient media were solely composed of brominated cyclic depsipeptides. Bromo-alterochromides A and B were obtained after cultivation on low nutrient media, while dibrominated derivatives were the principal components of the biosynthesis during cultivation on nutrient rich media. CONCLUSIONS: The quantity of bromo-alterochromides and their dibromo- derivates varied depending on the media composition. SIGNIFICANCE AND IMPACT OF THE STUDY: MALDI-TOF mass spectrometry enables to generate accurate mass analysis for the identification of peptide and its derivates which is important in controlling the production of biologically active compounds in vitro.

Animals↗
PubMed1995

Cyanopeptolin S, a sulfate-containing depsipeptide from a water bloom of Microcystis sp.

A new sulfated, cyclic depsipeptide, called cyanopeptolin S, from Microcystis sp. was isolated from a water bloom in the Auensee/Leipzig (Germany). The depsipeptide had a relative molecular mass of 925 and contained L-arginine, L-threonine, L-isoleucine, N-methyl-L-phenylalanine, a L-glutamic acid-delta-aldehyde ring system and a sulfated D-configurated glyceric acid as a side chain. The structure was elucidated by means of two-dimensional 1H and 13C nuclear magnetic resonance spectroscopy, fast atom bombardment mass spectroscopy. Fourier transformed infrared spectroscopy and combined gas-liquid chromatography/mass spectrometry. Cyanopeptolin S inhibited trypsin with an IC50 < or = 0.2 micrograms ml-1.

Bacterial Proteins↗
PubMed2004

Cell growth on the porous sponges prepared from poly(depsipeptide-co-lactide) having various functional groups.

In tissue engineering, excellent biodegradable materials are desired as temporary scaffolds to support cell growth and disappear with the progress of tissue regeneration. We previously synthesized biodegradable poly(depsipeptide-co-lactide), poly[(Glc-Asp)-co-LA] and poly[(Glc-Lys)-co-LA], having reactive side-chain groups. Then, the effects of reactive and ionic side-chain groups on cell attachment and growth were investigated using co-polymer films with various amounts of carboxyl or amino groups. In this study, to evaluate the utility of these co-polymers as functional scaffolds for tissue regeneration, 3-dimensional porous sponges were prepared by freeze-drying method and the effects of reactive and ionic side-chain groups on cell growth and degradation behavior were investigated using co-polymer sponges with various amounts of carboxyl or amino groups. Good cell growth was observed on the co-polymer sponges. During cell culture, the co-polymer sponges exhibited various degradation rates related to the depsipeptide unit content. Three-dimensional biodegradable polymer matrices with reactive surface, controllable degradation behavior and good cell growth were successfully prepared using these co-polymers. Such kinds of co-polymer matrices are good candidate for scaffold for tissue engineering.

Absorbable Implants↗
PubMed2003

Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines.

PURPOSE: Uveal melanoma (UM) is the most common primary malignant ocular tumor in adults. No effective chemotherapy regimens are available for either intraocular or metastatic uveal melanoma. Therefore, the ability of the histone deacetylase inhibitors (HDACIs), depsipeptide, sodium butyrate (NaB) and trichostatin A (TSA), to induce apoptosis and inhibit cell growth of UM cell lines in vitro was examined. METHODS: Three primary and two metastatic UM cell lines were treated in vitro with different concentrations of histone deacetylase inhibitors (HDACIs). Cell proliferation was studied in 24-well plates. Induction of apoptosis was studied by flow cytometry. Changes in gene expression of Fas/FasL, p21(Waf/Cip1), and p27(Kip1) were studied by RT-PCR. Western blot analysis was used to study histone acetylation, Fas/FasL, p21(Waf/Cip1), p27(Kip1) and caspase-3 protein levels. Real-time PCR was used to study changes in bcl-2/bax gene expression. RESULTS: A dose-dependent increase in histone acetylation was observed in all cell lines. This corresponded to significant inhibition of cell growth and induction of apoptosis in all melanoma cell lines in a concentration-dependent manner. Western blot analysis revealed dose-dependent increases in the amount of caspase-3, Fas/FasL, p21(Waf/Cip1), and p27(Kip1) proteins. However, no changes in bcl-2/bax gene expression were detected by real-time PCR. CONCLUSIONS: HDACIs are potent inhibitors of primary and metastatic UM cell growth in vitro. The apoptosis is probably mediated through the Fas/FasL signaling pathway, whereas bcl-2 appears not to be involved. These data support further clinical evaluation of depsipeptide and other HDACIs in patients with primary and metastatic UM.

Antibiotics, Antineoplastic↗
PubMed2001

Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report.

Depsipeptide, FR901228, has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In the laboratory, it has been shown to be a histone deacetylase (HDAC) inhibitor. In a phase I trial of depsipeptide conducted at the National Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a partial response, and 1 patient with peripheral T-cell lymphoma, unspecified, had a complete response. Sézary cells isolated from patients after treatment had increased histone acetylation. These results suggest that inhibition of HDAC is a novel and potentially effective therapy for patients with T-cell lymphoma.

Acetylation↗
PubMed2004

A review of depsipeptide and other histone deacetylase inhibitors in clinical trials.

The histone deacetylase inhibitors (HDIs) are a new class of antineoplastic agents currently being evaluated in clinical trials. While these agents have been studied extensively in the laboratory, only recently has their mechanism of action begun to be elucidated. Several structural classes of compounds have been shown to exert histone deacetylase inhibition, including sodium n-butyrate, suberoylanilide hydroxamic acid, LAQ824, CI-994, MS-275, and depsipeptide. The HDIs have been shown to induce differentiation, to decrease cell proliferation, and to induce cell death. HDIs are thought to exert their anti-neoplastic effects by altering the expression of genes that play a role in the control of cell growth, and transformation. The HDIs have specific and well-defined effects on cancer cells. Preliminary results from clinical trials suggest that these agents are very promising. While there were sporadic case reports of activity using the early generation HDIs, dramatic responses have recently been observed in patients with T-cell lymphomas treated with depsipeptide, one of the newer agents. With the well-defined molecular effects on cancer cells, surrogate markers can be analyzed for evidence of activity and efficacy using either tumor samples or normal tissue. Presented in this review are details from clinical trials with both earlier and newer generations of HDIs. Toxicities specific to this class of agents are outlined and possibilities for rational combination therapies are discussed.

Antineoplastic Agents↗
PubMed2004

A contribution to the nomenclature of depsipeptides.

Depsipeptides, also called peptolides, are a class of peptidic compounds in which an amide bond has been replaced with an ester bond. The literature does not clearly display rules for the nomenclature of such compounds. Here a method is proposed to transcribe drawn depsipeptide structures in one-line text.

Esters↗
PubMed1996

A continuous assay of hepatitis C virus protease based on resonance energy transfer depsipeptide substrates.

Hepatitis C virus (HCV) is the major causative agent of non-A non-B hepatitis, an important health problem with an estimated 50 million people infected worldwide. Among the possible targets for therapeutic intervention, the serine protease contained within the N-terminal region of nonstructural protein 3 (NS3 protease) is so far the best characterized. In vitro characterization of synthetic substrates based on all the natural cleavage sites (as well as a series of analogs) has consistently revealed poor kinetic parameters, making them unsuitable for sensitive high-throughput screening. To overcome these difficulties, we have recently developed depsipeptide substrates incorporating an ester bond between residues P1 and P&prime1. Due to ready transesterification of the scissile bond to the acyl-enzyme intermediate, these substrates showed very high kcat/Km values, enabling detection of activity with subnanomolar NS3 concentrations. We have used the same principle to synthesize internally quenched depsipeptide fluorogenic substrates based on resonance energy transfer between the donor/acceptor couple 5-[(2'-aminoethyl)amino]naphthalene sulfonic acid/4-[[4'-(dimethylamino)phenyl]azo]benzoic acid, and developed a continuous assay for NS3 activity. Substrate cleavage is linear with enzyme concentration: depending on the conditions chosen, we estimated a detection limit for NS3 between 1 nM and 250 pM. The suitability of the assay for evaluation of inhibitors was established using as competitor a tridecapeptide corresponding to the natural NS4A/4B cleavage site; this gave an IC50 of 30 microM, well in agreement with the previously found Km value (40 microM).

Chromatography, High Pressure Liquid↗
PubMed1996

Cyclic peptides and depsipeptides from cyanobacteria: a review.

An elaborate array of structurally-novel and biologically-active cyclic peptides and depsipeptides are found in blue-green algae (cyanobacteria). Several of these compounds possess structures that are similar to those of natural products from marine invertebrates. Most of these cyclic peptides and depsipeptides, such as the microcystins and the lyngbyatoxins, will probably only be useful as biochemical research tools. A few, however, have the potential for development into useful commercial products. For example, cryptophycin-1, a novel inhibitor of microtubule assembly from Nostoc sp GSV 224, shows impressive activity against a broad spectrum of solid tumors implanted in mice, including multidrug-resistant ones, and majusculamide C, a microfilament-depolymerizing agent from Lyngbya majuscula, shows potent fungicidal activity and may have use in the treatment of resistant fungal-induced diseases of domestic plants and agricultural crops.

Amino Acid Sequence↗
PubMed2002

Syntheses of depsipeptide analogues of the insect neuropeptide proctolin.

Four depsipeptide analogues of the insect neuropeptide proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH) have been prepared, containing a single ester linkage between Arg(1) and Tyr(2), Tyr(2) and Leu(3), and between Pro(4) and Thr(5), respectively. A didepsipentapeptide containing an ester linkage between Tyr(2) and Leu(3) and between Pro(4) and Thr(5), has also been prepared. The depsipeptide 4 is the first example of a backbone-modified proctolin analogue which shows full myotropic activity.

Animals↗