RESUMEN
Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.
Asunto(s)
Cianobacterias , Cianobacterias/metabolismo , Cianobacterias/química , Cianobacterias/genética , Humanos , Familia de Multigenes , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/metabolismoRESUMEN
The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies on this strain led to the discovery of several novel compounds such as hectochlorins and jamaicamides. However, bioinformatic analyses of its genome indicate the presence of numerous cryptic biosynthetic gene clusters that have yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was cocultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that coculture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.
Asunto(s)
Cianobacterias , Depsipéptidos , Candida albicans/genética , Técnicas de Cocultivo , Cianobacterias/química , Depsipéptidos/metabolismo , Familia de MultigenesRESUMEN
The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies of this strain led to the discovery of several novel compounds such as the hectochlorins and jamaicamides; however, bioinformatic analyses of its genome suggested that there were many more cryptic biosynthetic gene clusters yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was co-cultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that co-culture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.
RESUMEN
Columbamides are chlorinated acyl amide natural products, several of which exhibit cannabinomimetic activity. These compounds were originally discovered from a culture of the filamentous marine cyanobacterium Moorena bouillonii PNG5-198 collected from the coastal waters of Papua New Guinea. The columbamide biosynthetic gene cluster (BGC) had been identified using bioinformatics, but not confirmed by experimental evidence. Here, we report the heterologous expression in Anabaena (Nostoc) PCC 7120 of the 28.5 kb BGC that encodes for columbamide biosynthesis. The production of columbamides in Anabaena is investigated under several different culture conditions, and several new columbamide analogs are identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR). In addition to previously characterized columbamides A, B, and C, new columbamides I-M are produced in these experiments, and the structure of the most abundant monochlorinated analog, columbamide K (11), is fully characterized. The other new columbamide analogs are produced in only small quantities, and structures are proposed based on high-resolution-MS, MS/MS, and 1H NMR data. Overexpression of the pathway's predicted halogenases resulted in increased productions of di- and trichlorinated compounds. The most significant change in production of columbamides in Anabaena is correlated with the concentration of NaCl in the medium.
Asunto(s)
Anabaena , Nostoc , Anabaena/química , Anabaena/genética , Cromatografía Liquida , Familia de Multigenes , Nostoc/genética , Espectrometría de Masas en TándemRESUMEN
Microbial specialized metabolites are an important source of and inspiration for many pharmaceuticals, biotechnological products and play key roles in ecological processes. Untargeted metabolomics using liquid chromatography coupled with tandem mass spectrometry is an efficient technique to access metabolites from fractions and even environmental crude extracts. Nevertheless, metabolomics is limited in predicting structures or bioactivities for cryptic metabolites. Efficiently linking the biosynthetic potential inferred from (meta)genomics to the specialized metabolome would accelerate drug discovery programs by allowing metabolomics to make use of genetic predictions. Here, we present a k-nearest neighbor classifier to systematically connect mass spectrometry fragmentation spectra to their corresponding biosynthetic gene clusters (independent of their chemical class). Our new pattern-based genome mining pipeline links biosynthetic genes to metabolites that they encode for, as detected via mass spectrometry from bacterial cultures or environmental microbiomes. Using paired datasets that include validated genes-mass spectral links from the Paired Omics Data Platform, we demonstrate this approach by automatically linking 18 previously known mass spectra (17 for which the biosynthesis gene clusters can be found at the MIBiG database plus palmyramide A) to their corresponding previously experimentally validated biosynthetic genes (e.g., via nuclear magnetic resonance or genetic engineering). We illustrated a computational example of how to use our Natural Products Mixed Omics (NPOmix) tool for siderophore mining that can be reproduced by the users. We conclude that NPOmix minimizes the need for culturing (it worked well on microbiomes) and facilitates specialized metabolite prioritization based on integrative omics mining.
RESUMEN
Three new compounds, portobelamides A and B (1 and 2), 3-amino-2-methyl-7-octynoic acid (AMOYA) and hydroxyisovaleric acid (Hiva) containing cyclic depsipeptides, and one long chain lipopeptide caciqueamide (3), were isolated from a field-collection of a Caldora sp. marine cyanobacterium obtained from Panama as part of the Panama International Cooperative Biodiversity Group Program. Their planar structures were elucidated through analysis of 2D NMR and MS data, especially high resolution (HR) MS2/MS3 fragmentation methods. The absolute configurations of compounds 1 and 2 were deduced by traditional hydrolysis, derivative formation, and chromatographic analyses compared with standards. Portobelamide A (1) showed good cytotoxicity against H-460 human lung cancer cells (33% survival at 0.9 µM).
Asunto(s)
Antineoplásicos/farmacología , Cianobacterias/química , Depsipéptidos/química , Antineoplásicos/química , Organismos Acuáticos/química , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Depsipéptidos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , PanamáRESUMEN
Microbial natural products are important for the understanding of microbial interactions, chemical defense and communication, and have also served as an inspirational source for numerous pharmaceutical drugs. Tropical marine cyanobacteria have been highlighted as a great source of new natural products, however, few reports have appeared wherein a multi-omics approach has been used to study their natural products potential (i.e., reports are often focused on an individual natural product and its biosynthesis). This study focuses on describing the natural product genetic potential as well as the expressed natural product molecules in benthic tropical cyanobacteria. We collected from several sites around the world and sequenced the genomes of 24 tropical filamentous marine cyanobacteria. The informatics program antiSMASH was used to annotate the major classes of gene clusters. BiG-SCAPE phylum-wide analysis revealed the most promising strains for natural product discovery among these cyanobacteria. LCMS/MS-based metabolomics highlighted the most abundant molecules and molecular classes among 10 of these marine cyanobacterial samples. We observed that despite many genes encoding for peptidic natural products, peptides were not as abundant as lipids and lipopeptides in the chemical extracts. Our results highlight a number of highly interesting biosynthetic gene clusters for genome mining among these cyanobacterial samples.
Asunto(s)
Productos Biológicos/farmacología , Cianobacterias/química , Cromatografía Líquida de Alta Presión , Cianobacterias/genética , Genoma Bacteriano , Genómica , Biología Marina , Espectrometría de Masas , Metabolómica , Familia de Multigenes , Filogenia , Clima TropicalRESUMEN
Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.
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Antivirales/uso terapéutico , Productos Biológicos/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Infecciones por Virus ARN/tratamiento farmacológico , Animales , Desarrollo de Medicamentos , Genoma Viral , Humanos , Virus ARN/efectos de los fármacos , Virus ARN/enzimología , Virus ARN/fisiología , Replicación ViralRESUMEN
Filamentous marine cyanobacteria make a variety of bioactive molecules that are produced by polyketide synthases, nonribosomal peptide synthetases, and hybrid pathways that are encoded by large biosynthetic gene clusters. These cyanobacterial natural products represent potential drug leads; however, thorough pharmacological investigations have been impeded by the limited quantity of compound that is typically available from the native organisms. Additionally, investigations of the biosynthetic gene clusters and enzymatic pathways have been difficult due to the inability to conduct genetic manipulations in the native producers. Here we report a set of genetic tools for the heterologous expression of biosynthetic gene clusters in the cyanobacteria Synechococcus elongatus PCC 7942 and Anabaena (Nostoc) PCC 7120. To facilitate the transfer of gene clusters in both strains, we engineered a strain of Anabaena that contains S. elongatus homologous sequences for chromosomal recombination at a neutral site and devised a CRISPR-based strategy to efficiently obtain segregated double recombinant clones of Anabaena. These genetic tools were used to express the large 28.7 kb cryptomaldamide biosynthetic gene cluster from the marine cyanobacterium Moorena (Moorea) producens JHB in both model strains. S. elongatus did not produce cryptomaldamide; however, high-titer production of cryptomaldamide was obtained in Anabaena. The methods developed in this study will facilitate the heterologous expression of biosynthetic gene clusters isolated from marine cyanobacteria and complex metagenomic samples.
Asunto(s)
Anabaena/metabolismo , Edición Génica/métodos , Oligopéptidos/biosíntesis , Productos Biológicos/metabolismo , Cromatografía Líquida de Alta Presión , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Familia de Multigenes , Oligopéptidos/análisis , Péptido Sintasas/genética , Plásmidos/genética , Plásmidos/metabolismo , Sintasas Poliquetidas/genética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2-6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4'-hydroxy-6,7-dimethoxyisoflavone), and 5-7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Aspergillus/química , Glycine max/química , Isoflavonas/aislamiento & purificación , Lipopolisacáridos/antagonistas & inhibidores , 4-Butirolactona/análogos & derivados , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Acetilcolinesterasa , Animales , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/farmacología , Antiinflamatorios/farmacología , Aspergillus/fisiología , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Ciclohexanonas/aislamiento & purificación , Ciclohexanonas/farmacología , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Furocumarinas/aislamiento & purificación , Furocumarinas/farmacología , Genisteína/aislamiento & purificación , Genisteína/farmacología , Inflamación , Isoflavonas/farmacología , Lipopolisacáridos/farmacología , Ratones , Células RAW 264.7 , Glycine max/microbiologíaRESUMEN
A thiazole-containing cyclic depsipeptide with 11 amino acid residues, named pagoamide A (1), was isolated from laboratory cultures of a marine Chlorophyte, Derbesia sp. This green algal sample was collected from America Samoa, and pagoamide A was isolated using guidance by MS/MS-based molecular networking. Cultures were grown in a light- and temperature-controlled environment and harvested after several months of growth. The planar structure of pagoamide A (1) was characterized by detailed 1D and 2D NMR experiments along with MS and UV analysis. The absolute configurations of its amino acid residues were determined by advanced Marfey's analysis following chemical hydrolysis and hydrazinolysis reactions. Two of the residues in pagoamide A (1), phenylalanine and serine, each occurred twice in the molecule, once in the d- and once in the l-configuration. The biosynthetic origin of pagoamide A (1) was considered in light of other natural products investigations with coenocytic green algae.
Asunto(s)
Productos Biológicos/química , Chlorophyta/química , Depsipéptidos/química , Samoa Americana , Aminoácidos , Animales , Productos Biológicos/aislamiento & purificación , Depsipéptidos/aislamiento & purificación , Femenino , Estructura Molecular , Ratas , Espectrometría de Masas en TándemRESUMEN
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an important class of natural products that contain antibiotics and a variety of other bioactive compounds. The existing methods for discovery of RiPPs by combining genome mining and computational mass spectrometry are limited to discovering specific classes of RiPPs from small datasets, and these methods fail to handle unknown post-translational modifications. Here, we present MetaMiner, a software tool for addressing these challenges that is compatible with large-scale screening platforms for natural product discovery. After searching millions of spectra in the Global Natural Products Social (GNPS) molecular networking infrastructure against just eight genomic and metagenomic datasets, MetaMiner discovered 31 known and seven unknown RiPPs from diverse microbial communities, including human microbiome and lichen microbiome, and microorganisms isolated from the International Space Station.
Asunto(s)
Biología Computacional/métodos , Microbiota/genética , Procesamiento Proteico-Postraduccional/genética , Genómica/métodos , Humanos , Péptidos/química , Ribosomas/genética , Programas InformáticosRESUMEN
Nine new linear lipopeptides, microcolins E-M (1-9), together with four known related compounds, microcolins A-D (10-13), were isolated from the marine cyanobacterium Moorea producens using bioassay-guided and LC-MS/MS molecular networking approaches. Catalytic hydrogenation of microcolins A-D (10-13) yielded two known compounds, 3,4-dihydromicrocolins A and B (14, 15), and two new derivatives, 3,4-dihydromicrocolins C and D (16, 17), respectively. The structures of these new compounds were determined by a combination of spectroscopic and advanced Marfey's analysis. Structurally unusual amino acid units, 4-methyl-2-(methylamino)pent-3-enoic (Mpe) acid and 2-amino-4-methylhexanoic acid (N-Me-homoisoleucine), in compounds 1-3 and 8, respectively, are rare residues in naturally occurring peptides. These metabolites showed significant cytotoxic activity against H-460 human lung cancer cells with IC50 values ranging from 6 nM to 5.0 µM. The variations in structure and attendant biological activities provided fresh insights concerning structure-activity relationships for the microcolin class of lipopeptides.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Cianobacterias/química , Lipopéptidos/aislamiento & purificación , Biología Marina , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Lipopéptidos/química , Lipopéptidos/farmacologíaRESUMEN
Hybrid typeâ I PKS/NRPS biosynthetic pathways typically proceed in a collinear manner wherein one molecular building block is enzymatically incorporated in a sequence that corresponds to gene arrangement. In this work, genome mining combined with the use of a fluorogenic azide-based click probe led to the discovery and characterization of vatiamidesâ A-F, three structurally diverse alkynylated lipopeptides, and their brominated analogues, from the cyanobacterium Moorea producens ASI16Jul14-2. These derive from a unique combinatorial non-collinear PKS/NRPS system encoded by a 90â kb gene cluster in which an upstream PKS cassette interacts with three separate cognate NRPS partners. This is facilitated by a series of promiscuous intermodule PKS-NRPS docking motifs possessing identical amino acid sequences. This interaction confers a new type of combinatorial capacity for creating molecular diversity in microbial systems.
Asunto(s)
Lipopéptidos/biosíntesis , Péptido Sintasas/metabolismo , Secuencia de Aminoácidos , Química Clic , Cianobacterias/química , Cianobacterias/metabolismo , Lipopéptidos/química , Familia de Multigenes , Péptido Sintasas/química , Péptido Sintasas/genética , Alineación de SecuenciaRESUMEN
Dozens of type A malyngamides, principally identified by a decorated six-membered cyclohexanone headgroup and methoxylated lyngbic acid tail, have been isolated over several decades. Their environmental sources include macro- and microbiotic organisms, including sea hares, red alga, and cyanobacterial assemblages, but the true producing organism has remained enigmatic. Many type A analogues display potent bioactivity in human-health related assays, spurring an interest in this molecular class and its biosynthetic pathway. Here, we present the discovery of the type A malyngamide biosynthetic pathway in the first sequenced genome of the cyanobacterial genus Okeania. Bioinformatic analysis of two cultured Okeania genome assemblies identified 62 and 68 kb polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) pathways with unusual loading and termination genes. NMR data of malyngamide C acetate derived from 13C-substrate-fed cultures provided evidence that an intact octanoate moiety is transferred to the first KS module via a LipM homologue originally associated with lipoic acid metabolism and implicated an inactive ketoreductase (KR0) as critical for six-membered ring formation, a hallmark of the malyngamide family. Phylogenetic analysis and homology modeling of the penultimate KR0 domain inferred structural cofactor binding and active site alterations as contributory to domain dysfunction, which was confirmed by recombinant protein expression and NADPH binding assay. The carbonyl retained from this KR0 ultimately enables an intramolecular Knoevenagel condensation to form the characteristic cyclohexanone ring. Understanding this critical step allows assignment of a biosynthetic model for all type A malyngamides, whereby well-characterized tailoring modifications explain the surprising proliferation and diversity of analogues.
Asunto(s)
Ciclohexanonas/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Péptido Sintasas/metabolismo , Sintasas Poliquetidas/metabolismo , Ácido Acético/metabolismo , Secuencia de Aminoácidos , Vías Biosintéticas/efectos de los fármacos , Caprilatos/metabolismo , Isótopos de Carbono , Dominio Catalítico , Biología Computacional , Cianobacterias/química , Inhibidores Enzimáticos/farmacología , Glicina/metabolismo , Modelos Biológicos , Péptido Sintasas/química , Péptido Sintasas/genética , Filogenia , Sintasas Poliquetidas/química , Sintasas Poliquetidas/genética , Dominios Proteicos , Pirimidinas/farmacología , Alineación de SecuenciaRESUMEN
Decreasing sequencing costs has sparked widespread investigation of the use of microbial genomics to accelerate the discovery and development of natural products for therapeutic uses. Tropical marine filamentous cyanobacteria have historically produced many structurally novel natural products, and therefore present an excellent opportunity for the systematic discovery of new metabolites via the information derived from genomics and molecular genetics. Adequate knowledge transfer and institutional know-how are important to maintain the capability for studying filamentous cyanobacteria due to their unusual microbial morphology and characteristics. Here, we describe workflows, procedures, and commentary on sample collection, cultivation, genomic DNA generation, bioinformatics tools, and biosynthetic pathway analysis concerning filamentous cyanobacteria.
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Técnicas Bacteriológicas/métodos , Productos Biológicos/química , Cianobacterias/genética , Genoma Bacteriano , Biología Marina/métodos , Técnicas Bacteriológicas/instrumentación , Criopreservación , Medios de Cultivo/química , Cianobacterias/crecimiento & desarrollo , Cianobacterias/aislamiento & purificación , ADN Bacteriano/aislamiento & purificación , Buceo , Ecosistema , Marcaje Isotópico/métodos , Estructura Molecular , Familia de Multigenes , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Microbiología del Agua , Flujo de TrabajoRESUMEN
The unusual feature of a t-butyl group is found in several marine-derived natural products including apratoxin A, a Sec61 inhibitor produced by the cyanobacterium Moorea bouillonii PNG 5-198. Here, we determine that the apratoxin A t-butyl group is formed as a pivaloyl acyl carrier protein (ACP) by AprA, the polyketide synthase (PKS) loading module of the apratoxin A biosynthetic pathway. AprA contains an inactive "pseudo" GCN5-related N-acetyltransferase domain (ΨGNAT) flanked by two methyltransferase domains (MT1 and MT2) that differ distinctly in sequence. Structural, biochemical, and precursor incorporation studies reveal that MT2 catalyzes unusually coupled decarboxylation and methylation reactions to transform dimethylmalonyl-ACP, the product of MT1, to pivaloyl-ACP. Further, pivaloyl-ACP synthesis is primed by the fatty acid synthase malonyl acyltransferase (FabD), which compensates for the ΨGNAT and provides the initial acyl-transfer step to form AprA malonyl-ACP. Additionally, images of AprA from negative stain electron microscopy reveal multiple conformations that may facilitate the individual catalytic steps of the multienzyme module.
Asunto(s)
Proteínas Bacterianas/metabolismo , Carboxiliasas/metabolismo , Depsipéptidos/biosíntesis , Metiltransferasas/metabolismo , Enzimas Multifuncionales/metabolismo , Sintasas Poliquetidas/metabolismo , Proteína Transportadora de Acilo/metabolismo , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Carboxiliasas/química , Dominio Catalítico , Cianobacterias/química , Descarboxilación , Depsipéptidos/química , Depsipéptidos/aislamiento & purificación , Metilación , Metiltransferasas/química , Enzimas Multifuncionales/química , Sintasas Poliquetidas/química , Especificidad por SustratoRESUMEN
Cancer cell cytotoxicity was used to guide the isolation of nine new swinholide-related compounds, named samholides A-I (1-9), from an American Samoan marine cyanobacterium cf. Phormidium sp. Their structures were determined by extensive analysis of 1D and 2D NMR spectroscopic data. The new compounds share an unusual 20-demethyl 44-membered lactone ring composed of two monomers, and they demonstrate structural diversity arising from geometric isomerization of double bonds, sugar units with unique glyceryl moieties and varied methylation patterns. All of the new samholides were potently active against the H-460 human lung cancer cell line with IC50 values ranging from 170 to 910 nM. The isolation of these new swinholide-related compounds from a marine cyanobacterium reinvigorates questions concerning the evolution and biosynthetic origin of these natural products.
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Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Cianobacterias/metabolismo , Toxinas Marinas/metabolismo , Toxinas Marinas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Toxinas Marinas/químicaRESUMEN
We reported previously the discovery of the potent antimalarial 40-membered macrolide bastimolide A (1) from the tropical marine cyanobacterium Okeania hirsute. Continued investigation has led to the discovery of a new analogue, bastimolide B (2), a 24-membered polyhydroxy macrolide with a long aliphatic chain and unique terminal tert-butyl group. Its complete structure was determined by a combination of extensive spectroscopic methods and comparative analysis of its methanolysis products with those of bastimolide A. A methanolysis mechanism for bastimolide A is proposed, and one unexpected isomerization product of the C2-C3 double bond, 2-(E)-bastimolide A (3), was obtained. Bastimolide B (2) showed strong antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain HB3. A preliminary investigation of the structure-activity relationship based on six analogues revealed the importance of the double bond as well as the 1,3-diol and 1,3,5-triol functionalities.