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14 pages, 2818 KiB

Open AccessArticle

Structure-Activity Relationship Study of Majusculamide D: Overcoming Metabolic Instability and Severe Toxicity with a Fluoro Analogue

by Xiuhe Zhao, Xiaonan Xi, Mingxiao Zhang, Mengxue Lv, Xiang Zhang, Yaxin Lu, Liang Wang and Yue Chen

Mar. Drugs 2024, 22(12), 537; https://doi.org/10.3390/md22120537 - 29 Nov 2024

Cited by 3 | Viewed by 1324

Abstract

Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, [...] Read more.

Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two (1i and 1j) demonstrated IC₅₀ values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue 1n demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model. Full article

(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)

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31 pages, 6348 KiB

Open AccessReview

Anti-Infective Secondary Metabolites of the Marine Cyanobacterium Lyngbya Morphotype between 1979 and 2022

by Diaa T. A. Youssef, Shatha J. Mufti, Abeer A. Badiab and Lamiaa A. Shaala

Mar. Drugs 2022, 20(12), 768; https://doi.org/10.3390/md20120768 - 7 Dec 2022

Cited by 9 | Viewed by 3262

Abstract

Cyanobacteria ascribed to the genus Lyngbya (Family Oscillatoriaceae) represent a potential therapeutic gold mine of chemically and biologically diverse natural products that exhibit a wide array of biological properties. Phylogenetic analyses have established the Lyngbya ‘morpho-type’ as a highly polyphyletic group and have [...] Read more.

Cyanobacteria ascribed to the genus Lyngbya (Family Oscillatoriaceae) represent a potential therapeutic gold mine of chemically and biologically diverse natural products that exhibit a wide array of biological properties. Phylogenetic analyses have established the Lyngbya ‘morpho-type’ as a highly polyphyletic group and have resulted in taxonomic revision and description of an additional six new cyanobacterial genera in the same family to date. Among the most prolific marine cyanobacterial producers of biologically active compounds are the species Moorena producens (previously L. majuscula, then Moorea producens), M. bouillonii (previously L. bouillonii), and L. confervoides. Over the years, compounding evidence from in vitro and in vivo studies in support of the significant pharmaceutical potential of ‘Lyngbya’-derived natural products has made the Lyngbya morphotype a significant target for biomedical research and novel drug leads development. This comprehensive review covers compounds with reported anti-infective activities through 2022 from the Lyngbya morphotype, including new genera arising from recent phylogenetic re-classification. So far, 72 anti-infective secondary metabolites have been isolated from various Dapis, Lyngbya, Moorea, and Okeania species. These compounds showed significant antibacterial, antiparasitic, antifungal, antiviral and molluscicidal effects. Herein, a comprehensive literature review covering the natural source, chemical structure, and biological/pharmacological properties will be presented. Full article

(This article belongs to the Section Marine Chemoecology for Drug Discovery)

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18 pages, 2987 KiB

Open AccessArticle

Micrococcin P1 and P2 from Epibiotic Bacteria Associated with Isolates of Moorea producens from Kenya

by Thomas Dzeha, Michael John Hall and James Grant Burgess

Mar. Drugs 2022, 20(2), 128; https://doi.org/10.3390/md20020128 - 7 Feb 2022

Cited by 3 | Viewed by 3783

Abstract

Epibiotic bacteria associated with the filamentous marine cyanobacterium Moorea producens were explored as a novel source of antibiotics and to establish whether they can produce cyclodepsipeptides on their own. Here, we report the isolation of micrococcin P1 (1) (C₄₈H [...] Read more.

Epibiotic bacteria associated with the filamentous marine cyanobacterium Moorea producens were explored as a novel source of antibiotics and to establish whether they can produce cyclodepsipeptides on their own. Here, we report the isolation of micrococcin P1 (1) (C₄₈H₄₉N₁₃O₉S₆; obs. m/z 1144.21930/572.60381) and micrococcin P2 (2) (C₄₈H₄₇N₁₃O₉S₆; obs. m/z 1142.20446/571.60370) from a strain of Bacillus marisflavi isolated from M. producens’ filaments. Interestingly, most bacteria isolated from M. producens’ filaments were found to be human pathogens. Stalked diatoms on the filaments suggested a possible terrestrial origin of some epibionts. CuSO₄·5H₂O assisted differential genomic DNA isolation and phylogenetic analysis showed that a Kenyan strain of M. producens differed from L. majuscula strain CCAP 1446/4 and L. majuscula clones. Organic extracts of the epibiotic bacteria Pseudoalteromonas carrageenovora and Ochrobactrum anthropi did not produce cyclodepsipeptides. Further characterization of 24 Firmicutes strains from M. producens identified extracts of B. marisflavi as most active. Our results showed that the genetic basis for synthesizing micrococcin P1 (1), discovered in Bacillus cereus ATCC 14579, is species/strain-dependent and this reinforces the need for molecular identification of M. producens species worldwide and their epibionts. These findings indicate that M. producens-associated bacteria are an overlooked source of antimicrobial compounds. Full article

(This article belongs to the Special Issue Natural Product Genomics and Metabolomics of Marine Bacteria)

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6 pages, 1048 KiB

Open AccessCommunication

Isolation and Structure Elucidation of a Novel Symmetrical Macrocyclic Phthalate Hexaester

by Michiya Kamio, Weina Jiang, Hiroki Osada, Masayuki Fukuoka, Hajime Uchida, Ryuichi Watanabe, Toshiyuki Suzuki and Hiroshi Nagai

Symmetry 2021, 13(2), 361; https://doi.org/10.3390/sym13020361 - 23 Feb 2021

Cited by 1 | Viewed by 2584

Abstract

A novel symmetrical macrocyclic phthalate hexaester (1) and a known macrocyclic phthalate tetraester (2) were isolated during a natural product-exploring program on the cyanobacterium Moorea producens. Their structures were elucidated based on spectroscopic data, including nuclear magnetic resonance [...] Read more.

A novel symmetrical macrocyclic phthalate hexaester (1) and a known macrocyclic phthalate tetraester (2) were isolated during a natural product-exploring program on the cyanobacterium Moorea producens. Their structures were elucidated based on spectroscopic data, including nuclear magnetic resonance and high-resolution mass spectra. In the antibacterial activity test, compounds 1 and 2 showed no bioactivity at the concentrations tested. Full article

(This article belongs to the Special Issue Recent Advances in the Analysis, Distribution and Functions of Enantiomers and Regioisomers of Biomolecules)

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14 pages, 1672 KiB

Open AccessArticle

Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium Moorea producens

by Anne Marie Sweeney-Jones, Kerstin Gagaring, Jenya Antonova-Koch, Hongyi Zhou, Nazia Mojib, Katy Soapi, Jeffrey Skolnick, Case W. McNamara and Julia Kubanek

Mar. Drugs 2020, 18(3), 167; https://doi.org/10.3390/md18030167 - 18 Mar 2020

Cited by 41 | Viewed by 5570

Abstract

A new cyclic peptide, kakeromamide B (1), and previously described cytotoxic cyanobacterial natural products ulongamide A (2), lyngbyabellin A (3), 18E-lyngbyaloside C (4), and lyngbyaloside (5) were identified from an antimalarial [...] Read more.

A new cyclic peptide, kakeromamide B (1), and previously described cytotoxic cyanobacterial natural products ulongamide A (2), lyngbyabellin A (3), 18E-lyngbyaloside C (4), and lyngbyaloside (5) were identified from an antimalarial extract of the Fijian marine cyanobacterium Moorea producens. Compounds 1 and 2 exhibited moderate activity against Plasmodium falciparum blood-stages with EC₅₀ values of 0.89 and 0.99 µM, respectively, whereas 3 was more potent with an EC₅₀ value of 0.15 nM. Compounds 1, 4, and 5 displayed moderate liver-stage antimalarial activity against P. berghei liver schizonts with EC₅₀ values of 1.1, 0.71, and 0.45 µM, respectively. The threading-based computational method FINDSITE^comb2.0 predicted the binding of 1 and 2 to potentially druggable proteins of Plasmodium falciparum, prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B (1) was predicted to bind to several Plasmodium actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria III)

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7 pages, 895 KiB

Open AccessFeature PaperCommunication

Neo-Aplysiatoxin A Isolated from Okinawan Cyanobacterium Moorea Producens

by Mioko Kawaguchi, Masayuki Satake, Bo-Tao Zhang, Yue-Yun Xiao, Masayuki Fukuoka, Hajime Uchida and Hiroshi Nagai

Molecules 2020, 25(3), 457; https://doi.org/10.3390/molecules25030457 - 22 Jan 2020

Cited by 23 | Viewed by 3730

Abstract

A new aplysiatoxin derivative, neo-aplysiatoxin A (1), along with seven known compounds, neo-debromoaplysiatoxin A (2), dolastatin 3 (3), lyngbic acid (4), malyngamide M (5), hermitamide A (6), (−)-loliolide (7), [...] Read more.

A new aplysiatoxin derivative, neo-aplysiatoxin A (1), along with seven known compounds, neo-debromoaplysiatoxin A (2), dolastatin 3 (3), lyngbic acid (4), malyngamide M (5), hermitamide A (6), (−)-loliolide (7), and (+)-epiloliolide (8), was isolated from the Okinawan cyanobacterium Moorea producens. Their structures were elucidated on the basis of spectroscopic data, including high-resolution mass spectrometry and nuclear magnetic resonance. The compounds were evaluated for cytotoxic and diatom growth inhibition activities. Full article

(This article belongs to the Special Issue Bioactive Compounds from Cyanobacteria)

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7 pages, 708 KiB

Open AccessEditor’s ChoiceCommunication

Oscillatoxin I: A New Aplysiatoxin Derivative, from a Marine Cyanobacterium

by Hiroshi Nagai, Shingo Sato, Kaori Iida, Kazutaka Hayashi, Mioko Kawaguchi, Hajime Uchida and Masayuki Satake

Toxins 2019, 11(6), 366; https://doi.org/10.3390/toxins11060366 - 21 Jun 2019

Cited by 37 | Viewed by 4637

Abstract

Cyanobacteria have been shown to produce a number of bioactive compounds, including toxins. Some bioactive compounds obtained from a marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) have been recognized as drug leads; one of these compounds is aplysiatoxin. We have isolated various [...] Read more.

Cyanobacteria have been shown to produce a number of bioactive compounds, including toxins. Some bioactive compounds obtained from a marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) have been recognized as drug leads; one of these compounds is aplysiatoxin. We have isolated various aplysiatoxin derivatives from a M. producens sample obtained from the Okinawan coastal area. The frozen sample was extracted with organic solvents. The ethyl acetate layer was obtained from the crude extracts via liquid–liquid partitioning, then separated by HPLC using a reversed-phase column. Finally, 1.1 mg of the compound was isolated. The chemical structure of the isolated compound was elucidated with spectroscopic methods, using HR-MS and 1D and 2D NMR techniques, and was revealed to be oscillatoxin I, a new member of the aplysiatoxin family. Oscillatoxin I showed cytotoxicity against the L1210 mouse lymphoma cell line and diatom growth-inhibition activity against the marine diatom Nitzschia amabilis. Full article

(This article belongs to the Special Issue Marine Toxins Detection)

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13 pages, 2493 KiB

Open AccessFeature PaperArticle

Three New Malyngamides from the Marine Cyanobacterium Moorea producens

by Kosuke Sueyoshi, Aki Yamano, Kaori Ozaki, Shimpei Sumimoto, Arihiro Iwasaki, Kiyotake Suenaga and Toshiaki Teruya

Mar. Drugs 2017, 15(12), 367; https://doi.org/10.3390/md15120367 - 29 Nov 2017

Cited by 26 | Viewed by 6266

Abstract

Three new compounds of the malyngamide series, 6,8-di-O-acetylmalyngamide 2 (1), 6-O-acetylmalyngamide 2 (2), and N-demethyl-isomalyngamide I (3), were isolated from the marine cyanobacterium Moorea producens. Their structures were determined by spectroscopic [...] Read more.

Three new compounds of the malyngamide series, 6,8-di-O-acetylmalyngamide 2 (1), 6-O-acetylmalyngamide 2 (2), and N-demethyl-isomalyngamide I (3), were isolated from the marine cyanobacterium Moorea producens. Their structures were determined by spectroscopic analysis and chemical derivatization and degradation. These compounds stimulated glucose uptake in cultured L6 myotubes. In particular, 6,8-di-O-acetylmalyngamide 2 (1) showed potent activity and activated adenosine monophosphate-activated protein kinase (AMPK). Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies in Asia)

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9 pages, 785 KiB

Open AccessArticle

New Cerebroside and Nucleoside Derivatives from a Red Sea Strain of the Marine Cyanobacterium Moorea producens

by Diaa T.A. Youssef, Sabrin R.M. Ibrahim, Lamiaa A. Shaala, Gamal A. Mohamed and Zainy M. Banjar

Molecules 2016, 21(3), 324; https://doi.org/10.3390/molecules21030324 - 9 Mar 2016

Cited by 18 | Viewed by 6216

Abstract

In the course of our ongoing efforts to identify marine-derived bioactive compounds, the marine cyanobacterium Moorea producens was investigated. The organic extract of the Red Sea cyanobacterium afforded one new cerebroside, mooreaside A (1), two new nucleoside derivatives, 3-acetyl-2′-deoxyuridine (2) and 3-phenylethyl-2′-deoxyuridine (3), [...] Read more.

In the course of our ongoing efforts to identify marine-derived bioactive compounds, the marine cyanobacterium Moorea producens was investigated. The organic extract of the Red Sea cyanobacterium afforded one new cerebroside, mooreaside A (1), two new nucleoside derivatives, 3-acetyl-2′-deoxyuridine (2) and 3-phenylethyl-2′-deoxyuridine (3), along with the previously reported compounds thymidine (4) and 2,3-dihydroxypropyl heptacosanoate (5). The structures of the compounds were determined by different spectroscopic studies (UV, IR, 1D, 2D NMR, and HRESIMS), as well as comparison with the literature data. Compounds 1–5 showed variable cytotoxic activity against three cancer cell lines. Full article

(This article belongs to the Collection Bioactive Compounds)

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17 pages, 989 KiB

Open AccessArticle

Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells

by J. Brian Morgan, Yang Liu, Veena Coothankandaswamy, Fakhri Mahdi, Mika B. Jekabsons, William H. Gerwick, Frederick A. Valeriote, Yu-Dong Zhou and Dale G. Nagle

Mar. Drugs 2015, 13(3), 1552-1568; https://doi.org/10.3390/md13031552 - 20 Mar 2015

Cited by 42 | Viewed by 8304

Abstract

The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-d-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed [...] Read more.

The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-d-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line- and exposure time-dependent cytostatic/cytotoxic effects were previously observed with mitochondria-targeted inhibitors of hypoxia-inducible factor-1 (HIF-1). The transcription factor HIF-1 functions as a key regulator of oxygen homeostasis. Therefore, we investigated the ability of kalkitoxin to inhibit hypoxic signaling in human tumor cell lines. Kalkitoxin potently and selectively inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC₅₀ 5.6 nM). Mechanistic studies revealed that kalkitoxin inhibits HIF-1 activation by suppressing mitochondrial oxygen consumption at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Further studies indicate that kalkitoxin targets tumor angiogenesis by blocking the induction of angiogenic factors (i.e., VEGF) in tumor cells. Full article

(This article belongs to the Collection Marine Compounds and Cancer)

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17 pages, 1071 KiB

Open AccessArticle

Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons

by Zhengyu Cao, Xichun Li, Xiaohan Zou, Michael Greenwood, William H. Gerwick and Thomas F. Murray

Mar. Drugs 2015, 13(2), 903-919; https://doi.org/10.3390/md13020903 - 10 Feb 2015

Cited by 15 | Viewed by 7156

Abstract

The frequent occurrence of Moorea producens (formerly Lyngbya majuscula) blooms has been associated with adverse effects on human health. Hoiamide A is a structurally unique cyclic depsipeptide isolated from an assemblage of the marine cyanobacteria M. producens and Phormidium gracile. [...] Read more.

The frequent occurrence of Moorea producens (formerly Lyngbya majuscula) blooms has been associated with adverse effects on human health. Hoiamide A is a structurally unique cyclic depsipeptide isolated from an assemblage of the marine cyanobacteria M. producens and Phormidium gracile. We examined the influence of hoiamide A on neurite outgrowth in neocortical neurons and found that it suppressed neurite outgrowth with an IC₅₀ value of 4.89 nM. Further study demonstrated that hoiamide A stimulated lactic acid dehydrogenase (LDH) efflux, nuclear condensation and caspase-3 activity with EC₅₀ values of 3.66, 2.55 and 4.33 nM, respectively. These data indicated that hoiamide A triggered a unique neuronal death profile that involves both necrotic and apoptotic mechanisms. The similar potencies and similar time-response relationships between LDH efflux and caspase-3 activation/nuclear condensation suggested that both necrosis and apoptosis may derive from interaction with a common molecular target. The broad-spectrum caspase inhibitor, Z-VAD-FMK completely inhibited hoiamide A-induced neurotoxicity. Additionally, hoiamide A stimulated JNK phosphorylation, and a JNK inhibitor attenuated hoiamide A-induced neurotoxicity. Collectively, these data demonstrate that hoiamide A-induced neuronal death requires both JNK and caspase signaling pathways. The potent neurotoxicity and unique neuronal cell death profile of hoiamide A represents a novel neurotoxic chemotype from marine cyanobacteria. Full article

(This article belongs to the Special Issue Emerging Marine Toxins)

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13 pages, 595 KiB

Open AccessCommunication

Two New Lyngbyatoxin Derivatives from the Cyanobacterium, Moorea producens

by Weina Jiang, Satoshi Tan, Yusuke Hanaki, Kazuhiro Irie, Hajime Uchida, Ryuichi Watanabe, Toshiyuki Suzuki, Bryan Sakamoto, Michiya Kamio and Hiroshi Nagai

Mar. Drugs 2014, 12(12), 5788-5800; https://doi.org/10.3390/md12125788 - 1 Dec 2014

Cited by 22 | Viewed by 6424

Abstract

The toxin-producing cyanobacterium, Moorea producens, is a known causative organism of food poisoning and seaweed dermatitis (also known as “swimmer’s itch”). Two new toxic compounds were isolated and structurally elucidated from an ethyl acetate extract of M. producens collected from Hawaii. Analyses [...] Read more.

The toxin-producing cyanobacterium, Moorea producens, is a known causative organism of food poisoning and seaweed dermatitis (also known as “swimmer’s itch”). Two new toxic compounds were isolated and structurally elucidated from an ethyl acetate extract of M. producens collected from Hawaii. Analyses of HR-ESI-MS and NMR spectroscopies, as well as optical rotations and CD spectra indicated two new lyngbyatoxin derivatives, 2-oxo-3(R)-hydroxy-lyngbyatoxin A (1) and 2-oxo-3(R)-hydroxy-13-N-desmethyl-lyngbyatoxin A (2). The cytotoxicity and lethal activities of 1 and 2 were approximately 10- to 150-times less potent than lyngbyatoxin A. Additionally, the binding activities of 1 and 2 possessed 10,000-times lower affinity for the protein kinase Cδ (PKCδ)-C1B peptide when compared to lyngbyatoxin A. These findings suggest that these new lyngbyatoxin derivatives may mediate their acute toxicities through a non-PKC activation pathway. Full article

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12 pages, 614 KiB

Open AccessCommunication

A New Lyngbyatoxin from the Hawaiian Cyanobacterium Moorea producens

by Weina Jiang, Wei Zhou, Hajime Uchida, Masayuki Kikumori, Kazuhiro Irie, Ryuichi Watanabe, Toshiyuki Suzuki, Bryan Sakamoto, Michiya Kamio and Hiroshi Nagai

Mar. Drugs 2014, 12(5), 2748-2759; https://doi.org/10.3390/md12052748 - 12 May 2014

Cited by 36 | Viewed by 8238

Abstract

Lyngbyatoxin A from the marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) is known as the causative agent of “swimmer’s itch” with its highly inflammatory effect. A new toxic compound was isolated along with lyngbyatoxin A from an ethyl acetate extract of M. [...] Read more.

Lyngbyatoxin A from the marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) is known as the causative agent of “swimmer’s itch” with its highly inflammatory effect. A new toxic compound was isolated along with lyngbyatoxin A from an ethyl acetate extract of M. producens collected from Hawaii. Analyses of HR-ESI-MS and NMR spectroscopies revealed the isolated compound had the same planar structure with that of lyngbyatoxin A. The results of optical rotation and CD spectra indicated that the compound was a new lyngbyatoxin A derivative, 12-epi-lyngbyatoxin A (1). While 12-epi-lyngbyatoxin A showed comparable toxicities with lyngbyatoxin A in cytotoxicity and crustacean lethality tests, it showed more than 100 times lower affinity for protein kinase Cδ (PKCδ) using the PKCδ-C1B peptide when compared to lyngbyatoxin A. Full article

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