Antineoplastic Diterpene−Benzoate Macrolides from the Fijian Red Alga <i>Callophycus serratus</i>

Kubanek, Julia; Prusak, Anne C.; Snell, Terry W.; Giese, Rachel; Hardcastle, Kenneth I.; Fairchild, Craig R.; Aalbersberg, William G.L.; Raventós-Suárez, Carmen; Hay, Mark E.

doi:10.1021/ol052121f

Cited by 76 publications

(145 citation statements)

References 8 publications

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“…32 The presence of this compound in Callophycus sp. has been proposed in the past to rationalize the biosynthesis of the many meroditerpenes isolated from members of this red algal genus since 2005, 33 but was not previously detected. 27 This finding thus encouraged us to propose a biosynthetic pathway for iodocallophycoic acid A ( 1 ), iodocallophycols ( 2–5 ) and related bromophycoic acids.…”

Section: Resultsmentioning

confidence: 99%

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

et al. 2017

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Unique iodine-containing meroditerpenes io-docallophycoic acid A (1) and iodocallophycols A–D (2–5) were discovered from the Fijian red alga Callophycus sp. Because flexibility of the molecular skeleton impaired full characterization of relative stereochemistries by NMR spectroscopy, a DFT-based theoretical model was developed to derive relevant interproton distances which were compared to those calculated from NOE measurements, yielding the relative stereochemistries. The correct 2S,6S,7S,10S,14S enantiomers were then identified by comparison of theoretical and experimental ECD spectra. Biological activities of these iodinated and brominated meroditerpenes and additional new, related bromophycoic acid F (6) and bromophycoic acid A methyl ester (7), were evaluated for relevant human disease targets. Iodocallophycoic acid A (1) showed moderate antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) with MIC values of 1.4 and 2.2 μg mL−1, respectively. It also potentiated the anti-MRSA activity of oxacillin in a synergistic fashion, resulting in an 8-fold increase in oxacillin potency, for a MIC of 16 μg mL−1.

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Section: Resultsmentioning

confidence: 99%

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

et al. 2017

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“…As previously described [20], these bacteria were grown in GYT media (1 g glucose, 2.5 g yeast extract, 5.0 g tryptone, 1 L H2O) overnight at 37°C. Cultures were diluted to an optical density of 0.04-0.06, diluted 10-fold, and then 250 μg/ml of extracts were added to microtiter plates.…”

Section: Methodsmentioning

confidence: 99%

High content live cell imaging for the discovery of new antimalarial marine natural products

et al. 2012

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BackgroundThe human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.MethodsA high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.ResultsImage analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.ConclusionCollectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.

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“…2 Given that no other differences between 1 and 8 were apparent, we predict that 1 shares the absolute stereochemistry of 8. 2,4 Bromophycolide D (2) also seemed to be structurally similar to 8, with an identical molecular formula (C 27 H 37 O 4 Br 3 from [M-H] − m/z 661.0190). The difference occurred near the diterpene-aryl junction, where instead of a tetra-substituted olefin at C-6-C-19 as in 8, DEPT and HSQC analysis indicated an exo-methylene group (C-23).…”

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Bromophycolides C−I from the Fijian Red Alga Callophycus serratus

et al. 2006

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Bromophycolides C-I (1−7) were isolated from extracts of the Fijian red alga Callophycus serratus, and identified by NMR and mass spectral techniques. These novel natural products share a carbon skeleton and biosynthetic origin with previously identified bromophycolides A (8) and B (9), which form a rare group of diterpene-benzoate macrolides. Bromophycolides C-I (1−7) displayed modest antineoplastic activity against a range of human tumor cell lines.Marine red algae have been the source of numerous isoprenoid and phenolic metabolites, 1 although natural products of combined isoprenoid and shikimate biosynthetic origin are less common. As part of a continuing investigation of bioactive substances from Fijian coral reef organisms, we recently reported the identification of three structurally unusual diterpenebenzoate macrolides from the red alga Callophycus serratus. 2 Herein, we provide data in support of the identification of seven related compounds, bromophycolides C-F (1−7), whose structures were elucidated by NMR and mass spectral analyses and by comparison with previously isolated bromophycolides A-B (8−9) and debromophycolide A (10). Results and discussionGuided by a toxicity assay using ingestion rates of the invertebrate Brachionus calyciflorus (Rotifera), 3 extracts of Callophycus serratus were separated by liquid-liquid partitioning, reversed-phase HPLC, and normal-phase HPLC, yielding bromophycolides C-I (1−7), which each represented 0.027−0.092% of algal dry mass (see Experimental section for details).Bromophycolide C (1), with an ESI molecular ion of m/z 599.1010 suitable for molecular formula C 27 H 38 O 5 Br 2 , appeared to differ from previously identified bromophycolide A (8) 2 only by the substitution of a bromine for a hydroxyl group. Comparison of NMR spectral data for 1 (Table 1 ; Supporting information) and for 8 2 suggested that the sole difference lay near the diterpene head. Specifically, the resonance for C-15 of 8 occurred at δ 67.3, compared with δ 72.0 in 1. Position 14, curiously, was not greatly affected ( 13 C δ 81.7 vs. 80.4; 1 H δ 4.75 vs. 4.65, for 1 and 8, respectively), but 13 C chemical shifts for positions 13, 26, and 27 in 1 were *To whom correspondence should be addressed: telephone: 404−894−8424; fax: 404−385−4440; email: julia.kubanek@biology.gatech.edu. Supporting Information Available: COSY, HMBC, and NOE data, and 1 H NMR spectra for 1−7, available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 2−7 ppm downfield relative to these positions in 8. All other 13 C and 1 H chemical shifts for 1 and 8 were within ca. 1 ppm. 1 H-1 H scalar couplings were also very similar for 1 and 8, suggesting that their relative configurations did not differ. In particular, H-14 appeared as a doublet of doublets (J=2 and 11 Hz) for both 1 and 8, establishing a common dihedral relationship to the two H-13 protons, consistent with the 14S configuration previously confirmed by the X...

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Antineoplastic Diterpene−Benzoate Macrolides from the Fijian Red Alga Callophycus serratus

Cited by 76 publications

References 8 publications

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

High content live cell imaging for the discovery of new antimalarial marine natural products

Bromophycolides C−I from the Fijian Red Alga Callophycus serratus

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