As part of our continuing interest in exploring the chemistry of actinomycete bacteria uniquely adapted for survival in ocean sediments, we encountered several new strains, which by 16S rDNA sequence-based phylogenetic analysis were recognized as members of a new genus (tentatively called MAR4) within the family Streptomycetaceae. We report here the isolation and structure elucidation of three new chlorinated dihydroquinones (1-3) and one previously reported analogue, 4, from our strain CNQ-525, isolated from ocean sediments collected at a depth of 152 m near La Jolla, California. The compounds formally possess new carbon skeletons, but are related to several previously reported metabolites of the napyradiomycin class. The structures of the new molecules, which possess significant antibiotic properties and cancer cell cytotoxicities, were assigned by comprehensive spectral measurements and by comparison with NMR and other spectral data from the antibiotic A80915C (5), the full stereostructure of which was recently assigned by X-ray diffraction methods.
Palmyrolide A (1) is a new neuroactive macrolide isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf. and Oscillatoria spp. collected from Palmyra Atoll. It features a rare N-methyl enamide and an intriguing t-butyl branch; the latter renders the adjacent lactone ester bond resistant to hydrolysis. Consistent with its significant suppression of calcium influx in cerebrocortical neurons (IC 50 =3.70 µM), palmyrolide A (1) showed relatively potent sodium channel blocking activity in neuro-2a cells (IC 50 =5.2 µM), without appreciable cytotoxicity.Suppression and/or activation of spontaneous Ca 2+ oscillations of murine cerebrocortical neurons1 has proven to be an extremely sensitive screening method for the discovery of new neurotoxins, including the recently reported cyanobacterial metabolites hoiamide A,2a alotamide A,2b and palmyramide A.2c In the case of hoiamide A, further pharmacological characterization found it to be a partial agonist at neurotoxin site 2 of voltage-gated sodium channels (VGSCs).2aPrimary cultures of cerebrocortical neurons allow the detection of two distinct actions when cells are loaded with the Ca 2+ sensitive fluorescent dye, fluo-3.1 First, those metabolites that trigger Ca 2+ influx can be easily revealed by monitoring for this ion using a Fluorometric Imaging Plate Reader (FLIPR). Secondly, because these cultures display spontaneous Ca 2+ oscillations, they provide a robust screening system for the discovery of small molecule ion wgerwick@ucsd.edu. Supporting Information Available: Experimental, full NMR data of 1, 2 and 4 (all stereoisomers), bioassay data, and taxonomic characterization. This material is available free of charge via the Internet at http://pubs.acs.org. (Table 1 and SI) was an intense singlet at δ0.86 (nine protons), which could be attributed to three isochronous methyl groups comprising a t-butyl moiety.8 Also present were the methyl doublets at δ0.90 and δ1.21, as well as the N-methyl singlet at δ3.04. The 1 H NMR of 1 was completed by a deshielded methine proton at δ4.88 and a terminal 1,2-disubstituted vinylic system represented by protons at δ5.27 (dt) and δ6.47 (d). The presence of a t-butyl moiety was supported in the 13 C NMR spectrum of 1 by a very intense resonance at δ26.1, as well as a quaternary carbon at δ35.2. Additionally, the deshielded carbons at δ117.3 and δ130.6 were in agreement with a 1,2-disubstituted double bond, whereas the carbonyls at δ172.9 and δ175.3 indicated a total of two ester or/and amide functionalities. As detailed below, extensive analysis of these 1 H and 13 C NMR resonances using HSQC, HMBC, COSY and NOESY led us to deduce the planar structure of 1. NIH Public AccessThe intense singlet at δ0.86 (H9, H10, H11) showed HMBC correlations with the quaternary carbon C8 (δ35.2), oxymethine C7 (δ76.9), and methylene carbon C6 (δ35.6) ( Figure 1A). This last carbon was found by HSQC to bear the diastereotopic proton resonances H6a (δ1.38) and H6b (δ1.66), which according to the COSY spectrum, participa...
Resumen.-Las bacterias y algas marinas son una fuente inagotable de compuestos químicos que permiten producir una amplia variedad de metabolitos secundarios bioactivos. Las bacterias marinas se han convertido en objetivo importante para la industria de la biotecnología debido a la alta cantidad de compuestos bioactivos descubierto recientemente a partir de ellas. El objetivo de este estudio fue evaluar la actividad anticancerígena y antibacteriana de extractos de las algas marinas Egregia menziesii, Codium fragile, Sargassum muticum, Endarachne binghamiae, Centroceras clavulatum y Laurencia pacifica recolectadas en Bahía Todos Santos, México. Se obtuvieron extractos orgánicos a partir de las algas libres de bacterias y de las bacterias asociadas a su superficie. Para probar la actividad antibacteriana se emplearon las cepas patógenas Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis y Pseudomonas aeruginosa y para la actividad anticancerígena, células de carcinoma colorectal HCT-116. De la superficie de las algas marinas se aislaron 35 cepas bacterianas que se identificaron molecularmente y pertenecían a los phyla Firmicutes, Proteobacteria, y Actinobacteria. Las cepas Cc51 aislada de Centroceras clavulatum, Sm36 aislada de Sargassum muticum, y Eb46 aislada de Endarachne binghamiae mostraron actividad anticancerígena con un IC 50 de 6,492, 5,531 y 2,843 µg ml-1 respectivamente. Asimismo, los extractos de las bacterias asociadas a las algas marinas inhibieron el crecimiento de la bacteria Gram negativa Proteus mirabilis. La actividad biológica observada en este estudio ofrece la oportunidad de un análisis químico posterior, tal como el aislamiento de los compuestos activos responsables, a fin de contribuir en el descubrimiento de nuevos fármacos.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.