Cyanobacterium Symploca Research Articles

Triproamide and Pemukainalides, Cyclic Depsipeptides from the Marine Cyanobacterium Symploca hydnoides

A new cyclic depsipeptide, triproamide (1), containing the rare 4-phenylvaline (dolaphenvaline, Dpv) and a β-amino acid, dolamethylleucine (Dml), originally found in dolastatin 16, was isolated from the polar VLC-derived fraction of the extracts prepared from the marine cyanobacterium Symploca hydnoides. Triproamide (1) was isolated along with the known molecule kulokainalide-1 (2), as well as its two new analogues, pemukainalides A (3) and B (4). Their planar structures were elucidated based on extensive NMR and mass spectrometric data. The absolute and relative configurations of the compounds were determined utilizing a combination of Marfey's method, J-based configuration, and chiral-phase HPLC analyses. Kulokainalide-1 (2) and pemukainalide A (3) exhibited cytotoxicity against the MOLT-4 leukemia cell line with IC50 values of 5.9 and 5.6 μM, respectively.

Heptavalinamide A, an Extensively N-Methylated Linear Nonapeptide from a Cyanobacterium Symploca sp. and Development of a Highly Sensitive Analysis of N,N-Dimethylvaline by LCMS.

An extensively N-methylated linear nonapeptide heptavalinamide A (1) was isolated from the marine cyanobacterium Symploca sp. collected at Kabira Reef of Ishigaki Island, Okinawa. The amino acid sequence of 1 was assigned by interpretation of 2D NMR and MS/MS data. The absolute configurations of the constituent amino acids were determined by the application of Marfey's method. A method to assign the configuration of N,N-dimethylvaline by LCMS is discussed.

Trikoramide A, a Prenylated Cyanobactin from the Marine Cyanobacterium Symploca hydnoides.

A new cyclic decapeptide, trikoramide A (1), has been isolated from samples of the marine cyanobacterium Symploca hydnoides, collected from Bintan Island, Indonesia. Trikoramide A (1) is a C-prenylated cyclotryptophan-containing cyanobactin. Its planar structure was deduced by 1D and 2D NMR spectroscopy as well as HR-MS/MS data. In addition, its absolute configuration was determined by Marfey's method and 2D NOESY NMR spectroscopic analysis. Compound 1 possessed cytotoxicity against the MOLT-4 and AML2 cancer cell lines with IC50 values of 4.8 and 8.2 μM, respectively.

Croissamide, a proline-rich cyclic peptide with an N-prenylated tryptophan from a marine cyanobacterium Symploca sp.

Croissamide, a proline-rich cyclic peptide that contains an N-prenylated tryptophan, was isolated from a marine cyanobacterium Symploca sp. Its gross structure was determined by spectroscopic analyses, and the absolute configuration was established based on chiral HPLC analyses of acid hydrolysates.

Lipopeptides from the Tropical Marine Cyanobacterium Symploca sp.

A collection of the tropical marine cyanobacterium Symploca sp., collected near Kimbe Bay, Papua New Guinea, previously yielded several new metabolites including kimbeamides A–C, kimbelactone A, and tasihalide C. Investigations into a more polar cytotoxic fraction yielded three new lipopeptides, tasiamides C–E (1–3). The planar structures were deduced by 2D NMR spectroscopy and tandem mass spectrometry, and their absolute configurations were determined by a combination of Marfey’s and chiral-phase GC-MS analysis. These new metabolites are similar to several previously isolated compounds, including tasiamide (4), grassystatins (5, 6), and symplocin A, all of which were isolated from similar filamentous marine cyanobacteria.

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

The marine natural product malevamide D from the cyanobacterium Symploca hydnoides was synthesized for the first time. The final peptide coupling linked the dolaisoleuine and dolaproine subunits. The phenyl group of malevamide D was also functionalized with a photoreactive diazirine moiety, which was carried through seven reaction steps. Comprehensive assessment of the cytotoxicity in a panel of 42 human cancer cell lines revealed a geomean IC70 value of 1.5 nM (IC50 0.7 nM) for malevamide D, whereas the photoreactive derivative proved to be less active by a factor of at least 200. COMPARE analysis indicated tubulin interaction as likely mode of action of malevamide D.

Isolation and Structure Elucidation of Three New Lipopeptides from the Marine Cyanobacterium Symploca sp.

Isolation and Structure Elucidation of Three New Lipopeptides from the Marine Cyanobacterium Symploca sp.

The carmaphycins: new proteasome inhibitors exhibiting an α,β-epoxyketone warhead from a marine cyanobacterium.

Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α,β-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.

Symplocin A, a Linear Peptide from the Bahamian Cyanobacterium Symploca sp. Configurational Analysis of N,N-Dimethylamino Acids by Chiral-Phase HPLC of Naphthacyl Esters

The absolute stereostructures of the components of symplocin A (3), a new N,N-dimethyl-terminated peptide from the Bahamian cyanobacterium Symploca sp., were assigned from spectroscopic analysis, including MS, 2D NMR, and Marfey's analysis. The complete absolute configuration of symplocin A, including the unexpected D-configurations of the terminal N,N-dimethylisoleucine and valic acid residues, was assigned by chiral-phase HPLC of the corresponding 2-naphthacyl esters, a highly sensitive, complementary strategy for assignment of N-blocked peptide residues where Marfey's method is ineffectual or other methods fall short. Symplocin A exhibited potent activity as an inhibitor of cathepsin E (IC(50) 300 pM).

ChemInform Abstract: Synthetic Routes and Biological Evaluation of Largazole and Its Analogues as Potent Histone Deacetylase Inhibitors

AbstractReview: 21 refs.

Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.

Synthetic Routes and Biological Evaluation of Largazole and Its Analogues as Potent Histone Deacetylase Inhibitors

Natural products with interesting biological properties and structural diversity have often served as valuable lead drug candidates for the treatment of various human diseases. Largazole, isolated from the marine cyanobacterium Symploca sp. has exhibited potent inhibitory activity against many cancer cell lines. Besides, it shows remarkable selectivity between transformed and nontransformed cells, which is the main disadvantage of other antitumor natural products such as paclitaxel and actinomycin D. Due to its potential as a potent and selective anticancer drug candidate, a great deal of attention has been focused on largazole and its analogues. It is the aim of this review to highlight synthetic aspects of largazole and its analogues as well as their preliminary structure–activity relationship studies.

Isolation and Structure Determination of Malevamide E, a Dolastatin 14 Analogue, from the Marine Cyanobacterium Symploca laete-viridis

A new depsipeptide, malevamide E (1), was isolated from field-collected colonies of the filamentous cyanobacterium Symploca laete-viridis. The gross structure of 1 was determined by spectroscopic analyses, including one- and two-dimensional NMR and accurately measured MS/MS. Chiral HPLC analyses of an acid hydrolysate of 1 allowed the stereochemical assignments of its amino acid residues, which include N-methyl-L-alanine, alpha-N,gamma-N-dimethyl-L-asparagine, N-methyl-L-phenylalanine, L-proline, D-valine, and N-methyl-L-valine. LC-MS/MS analysis of S. laete-viridis fractions established the co-occurrence of malevamide E (1) and its homologue dolastatin 14 (2), which was previously reported in low yield from the sea hare Dolabella auricularia. Malevamide E (1) demonstrated a dose-dependent (2-45 microM) inhibition of store-operated Ca(2+) entry in thapsigargin-treated human embryonic kidney (HEK) cells, indicating an inhibitory effect on Ca(2+) release-activated Ca(2+) (CRAC) channels.

Structure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.

A novel cytotoxic cyclodepsipeptide, termed largazole (1), has been isolated from the marine cyanobacterium Symploca sp. collected in the Florida Keys. Its planar structure was elucidated by 1D and 2D NMR spectroscopy in conjunction with mass spectrometry. The absolute configuration of 1 was determined by chemical degradation followed by chiral HPLC analysis. Largazole (1) possesses densely assembled unusual structural features, including a rare 4-methylthiazoline linearly fused to a thiazole in its cyclic core and a hitherto undescribed 3-hydroxy-7-mercaptohept-4-enoic acid unit incorporated in an ester, thioester, and amide framework. Largazole (1) exhibits potent antiproliferative activity and preferentially targets cancer cells over nontransformed cells.

Belamide A, a new antimitotic tetrapeptide from a Panamanian marine cyanobacterium

The isolation and structure elucidation of belamide A from the marine cyanobacterium Symploca sp. is described. Belamide A is a highly methylated linear tetrapeptide with structural analogy to the important linear peptides dolastatins 10 and 15. Disruption of the microtubule network in A-10 cells was observed at 20 μM and displayed classic tubulin destabilizing antimitotic characteristics. The moderate cytotoxicity of belamide A (IC 50 0.74 μM vs HCT-116 colon cancer line) provides new insights into structure–activity relationships for this drug class.

The isolation and structure elucidation of Tasiamide B, a 4-amino-3-hydroxy-5-phenylpentanoic acid containing peptide from the marine Cyanobacterium Symploca sp.

A new cytotoxic peptide, which displayed an IC(50) value of 0.8 microM against KB cells, has been isolated from the marine cyanobacterium Symploca sp. The planar structure of tasiamide B (1), deduced by 2D NMR experiments, contains the unusual amino acid-derived residue 4-amino-3-hydroxy-5-phenylpentanoic acid (Ahppa). The configuration of 1 was deduced by HPLC analysis of degradation products.

Tasiamide, a cytotoxic peptide from the marine cyanobacterium Symploca sp.

The acyclic peptide tasiamide (1) has been isolated from the marine cyanobacterium Symploca sp. The planar structure and absolute stereochemistry of the peptide were deduced by 2D NMR techniques and chiral HPLC. Tasiamide (1) was cytotoxic against KB and LoVo cells with IC(50) values of 0.48 and 3.47 microg/mL, respectively.

Isolation of Dolastatin 10 from the Marine Cyanobacterium Symploca Species VP642 and Total Stereochemistry and Biological Evaluation of Its Analogue Symplostatin 1

The potent antitumor agent dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be L. Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.

Malevamides A-C, new depsipeptides from the marine cyanobacterium Symploca laete-viridis.

Three new depsipeptides, malevamides A-C (1-3), were isolated from the cyanobacterium Symploca laete-viridis collected off the south shore of Oahu, Hawaii. Compounds 1-3 were identified by spectral methods, and partial stereochemical assignments were made by chiral HPLC of the hydrolyzed compounds. At a concentration of 2 microg/mL, compounds 1-3 were inactive against P-388, A-549, and HT-29 cancer cells.

The presence and expression of hetR in the non-heterocystous cyanobacterium Symploca PCC 8002

The filamentous cyanobacteria Symploca PCC 8002 ( Symploca) and Trichodesmium spp. fix nitrogen aerobically in the light in a light/dark cycle, without forming specialized thick-walled cells (heterocysts). Even though they do not form heterocysts, we amplified and sequenced a segment of a key regulatory gene in heterocyst differentiation, the hetR gene, from Symploca, Trichodesmium erythraeum and Leptolyngbya PCC 73110 (which fixes nitrogen anaerobically) using degenerate oligonucleotides. The transcriptional level of hetR in Symploca PCC 8002 was examined in relation to nifH expression during nitrogen step-down. The expression pattern of hetR suggests that it was not induced during removal of combined nitrogen, as is the case with the heterocystous cyanobacteria. This is the first report of sequences corresponding to a portion of hetR from within the group of non-heterocystous cyanobacteria.