Bromophycolides C−I from the Fijian Red Alga Callophycus serratus

Abstract

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...

Antimalarial Bromophycolides J−Q from the Fijian Red Alga Callophycus serratus

“…COSY correlations between H-22 (δ 1.14) and both H-21 protons (δ 0.31, 0.42), between H-20 (δ 1.55) and both H-21 protons, and between H-22 and H-20, as well as the shielded chemical shift observed for methylene C-21 ( 13 C δ 8.5) prompted assignment of a cyclopropyl moiety comprised of C-20, C-21, and C-22. HMBC and COSY correlations established connection between this ring system and the benzoate system via C-5, analogous to previously identified metabolites 5,6…”

“…Comparison of 1 H, 13 C, HSQC, HMBC, and COSY NMR spectral data with known bromophycolides confirmed a 15-membered macrolide framework analogous to 1 and 9 (Supporting Information). 5,6 For 2 , a hydroxy substituent was assigned at C-15 (δ 72.1) on the basis of 13 C NMR chemical shift precedents 5,6. As with 1 , HMBC and COSY correlations suggested that 2 diverged from other bromophycolides within the terpene carbocyclic moiety.…”

“…From the Fijian red alga Callophycus serratus , we previously reported the discovery of ten bromophycolides, unusual C 27 diterpene-benzoate macrolides 5,6. Exploration of additional C. serratus collections then led to discovery of ten novel callophycoic acids and callophycols, C 27 diterpene-benzoic acids and C 26 diterpene-phenols 7.…”

Seaweed Allelopathy Against Coral: Surface Distribution of a Seaweed Secondary Metabolite by Imaging Mass Spectrometry

“…1B). Although many bioactive secondary metabolites have been isolated from C. densus , with several of these exhibiting antibacterial and antifungal activities (Kubanek et al, 2005, 2006; Lane et al, 2007, 2009), extracts from this alga did not significantly suppress photosynthesis or cause bleaching in corals. It is possible that compounds from this alga are not allelopathic, or that our bioassay methods degraded allelopathic compounds from this alga.…”

Unusual antimalarial meroditerpenes from tropical red macroalgae

“…Thus, the discovery of novel chemistry from natural sources could provide new scaffolds for the development of much needed antimalarial treatments. We previously discovered a structurally-novel class of brominated diterpenoid macrolides, called bromophycolides, from the Fijian red macroalga Callophycus serratus ,3–4 and several bromophycolides exhibited submicromolar activity against the human malaria parasite Plasmodium falciparum 5–6. Our continued efforts to uncover antimalarial natural products from understudied tropical red macroalgae led us to explore potent activity from two red algae in our library, thus leading to the identification of an unusual non-brominated macrolide we named callophycolide A ( 1 ) and two known tocopherols, β-tocopherylhydroquinone ( 4 ) and δ-tocopherylhydroquinone ( 5 ) from the coralline alga Amphiroa crassa .…”