Unprecedented antioxidative and anti-inflammatory aryl polyketides from the brown seaweed Sargassum wightii

https://doi.org/10.1016/j.foodres.2017.07.006Get rights and content

Highlights

  • Two new aryl polyketides were isolated from Sargassum wightii.

  • Represent aryl substituted oxo-2H-pyranyl and oxa-cyclododecadienyl macrolactone

  • Polyketide analogues showed comparable antioxidative activities with α-tocopherol.

  • Significantly greater anti-5-lipoxygenase activities of polyketides than ibuprofen

  • Formulated putative biosynthetic pathways of the title aryl polyketide lactones

Abstract

Previously undescribed aryl polyketide lactones, 4-(8-ethyl-tetrahydro-7-oxo-2H-pyran-5-yl)-propyl-4′-methylbenzoate (compound 1) and methyl-2-(12-oxo-7-phenyl-8-vinyl-1-oxa-4,9-cyclododecadien-3-yl)-acetate (compound 2) were purified from ethyl acetate-methanol fraction of the brown seaweed Sargassum wightii. The structures were proposed based on their NMR and mass spectrometric data. The antioxidative activities of the lactones were significantly greater (P < 0.05) (IC50 1,1-diphenyl-2-picrylhydrazyl radical scavenging 0.24–0.32 mg/mL) than α-tocopherol (IC50 0.63 mg/mL). The title compounds displayed considerably greater 5-lipoxygenase inhibitory activity (IC50 0.56 and 0.29 mg/mL, respectively) in conjunction with higher selectivity indices (anti-cycloxygense-1IC50/anti-cycloxygense-2IC50 > 1) compared to non-steroidal anti-inflammatory drugs (SIaspirin 0.03, SIibuprofen 0.43). Putative biosynthetic pathway of title polyketide products through polyketide synthase enzyme cascade catalyzed reactions substantiated the structural attributions of the hitherto unreported aryl polyketides. This is the first report of the occurrence and characterization of two rare skeletal types, oxo-2H-pyranyl and oxa-cyclododecadienyl macrolactone featuring the aryl substituent from marine organisms with potential antioxidative and anti-inflammatory activities.

Introduction

Seaweeds are acknowledged as prolific source of different classes of biologically active compounds suited for developing functional foods and pharmaceutical leads (Holdt & Kraan, 2011). Functional foods can provide health benefits by reducing the risk of chronic diseases and thus can improve the quality of life. The seaweed extracts with multiple functionalities could be incorporated into foods as natural preservatives to enhance the food quality, safety and stability (Vijayavel & Martinez, 2010). Oxidation of food, its additives and also oxidative stress induced diseases challenges mostly in the food safety and pharmaceutical field, thus the prevention of these requires more attention. Innovation of commercially viable seaweed based functional food and nutraceuticals procured more concern due to the negative impact of synthetic food and its supplements. Seaweeds have significant role in the optimization of health by providing novel bioactive components with anticancer, anti-HIV and antimicrobial activities (McGlacken & Fairlamb, 2005). The discovery of natural products with unprecedented carbon frameworks are important sources of novel synthetic leads. Macrolides, falls under the category of polyketides have been isolated from marine sources especially from seaweeds and seaweed associated bacteria (Chakraborty, Thilakan, & Raola, 2014). This group of compounds with their characteristic functional architecture can potentially bind to the target enzymes required to exhibit the bioactivities, and were therefore, found potential applications in discovery of more effective pharmacophores. Presently, the total number of commercially available drugs bearing macrocyclic framework are > 100 (Driggers, Hale, Lee, & Terrett, 2008). However, the chemistry of lactone macrocycles is continuously evolving with the probability to explore molecules with greater bioactivities compared to their ancestors. Seaweeds Phacelocarpus labillardieri and Neurymenia fraxinifolia were reported to produce polyketide group of macrolide pyrones, such as neurymenolides with potential antimicrobial activities against human pathogenic microorganisms (Kazlauskas et al., 1982, Stout et al., 2009). Antimicrobial and antineoplastic diterpene-benzoate macrolides and halogenated phycolides were isolated from the red seaweed Callophycus serratus (Kubanek et al., 2005). A 14-membered lactone derivative lactimidimycin, with a conjugated diene system was reported in a previous literature (Sugawara et al., 1992). Several bioactive natural products and synthetic compounds bearing tetrahydropryan skeleton are valuable pharmacophores for use against various lifestyle diseases (McDonald & Scheidt, 2015). Most of the reported lactones were terpenoid lactones and pyrone based macrolides (Kazlauskas et al., 1982, Kubanek et al., 2005).

Brown seaweeds are endowed with potential antioxidant (Chakraborty & Paulraj, 2010), antimicrobial (Valdebenito, Bittner, Sammes, Silva, & Watson, 1982) and anti-inflammatory properties (Maneesh, Chakraborty, & Makkar, 2017). Among different brown seaweeds, the genus Sargassum (family Sargassaceae) is one of the predominantly available brown seaweeds grown in the Gulf-of-Mannar region of the south-east coast of India. We have previously described the anti-diabetic, antihypertensive, anti-inflammatory and antioxidant potentials of the crude ethyl acetate-methanol extract (EtOAc/MeOH) derived from S. wightii (Maneesh et al., 2017). The present study aimed to isolate two unprecedented aryl polyketide lactones, named 4-(8-ethyl-tetrahydro-7-oxo-2H-pyran-5-yl)-propyl-4′-methylbenzoate (compound 1) and methyl-2-(12-oxo-7-phenyl-8-vinyl-1-oxa-4,9-cyclododecadien-3-yl)-acetate (compound 2) from the crude solvent extract, with the structures that has not been identified or postulated before. The structures of the titled compounds have been unambiguously characterized by extensive NMR and mass spectroscopic experiments. Anti-inflammatory and antioxidative characteristics of the compounds were assessed by in vitro pro-inflammatory anti-cyclooxygenase/lipoxygenase and radical scavenging assays, respectively. Different physicochemical attributes of the aryl polyketides purified from seaweed were used to corroborate the structure-activity correlations. Putative biosynthetic pathway of the polyketide products (compounds 1 and 2), through polyketide synthase enzyme cascade catalyzed reactions were evaluated to substantiate the structural attributions of the new aryl polyketides.

Section snippets

Instrumentation and chemicals

FT-IR (Fourier-transform infrared) spectra were documented on a Perkin-Elmer Series 2000 FT-IR spectrophotometer (Waltham, USA; scan range 400–4000 cm 1). Column chromatography was carried out using silica gel (60–120 and 230–400 mesh, E-Merck, Germany.). The GF254 plates (vanillin reagent sprayed) were used for TLC analysis. Varian Cary 50 UV-VIS spectrometer (Varian Cary, Walnut Creek, USA) was used to obtain UV spectroscopic data. Nuclear Magnetic Resonance (NMR) spectral analyses were

Chromatographic purification and spectral analysis of aryl polyketides

Bioactivity-guided repeated chromatographic purification of EtOAc/MeOH fraction resulted in the isolation of two previously undescribed aryl polyketide lactone derivatives, 4-(8-ethyl-tetrahydro-7-oxo-2H-pyran-5-yl) propyl-4′-methylbenzoate (compound 1) and methyl-2-(12-oxo-7-phenyl-8-vinyl-1-oxa-4, 9-cyclododecadien-3-yl)-acetate (compound 2). Structural characterizations of the purified compounds were performed by interpretation of combined two dimensional NMR (HSQC, 1Hsingle bond1H COSY, HMBC and

Conclusions

Two previously undescribed biogenic lactones titled as, 4-(8-ethyl-tetrahydro-7-oxo-2H-pyran-5-yl)-propyl-4-methylbenzoate and methyl-2-(12-oxo-7-phenyl-8-vinyl-1-oxa-4,9-cyclododecadien-3-yl)-acetate were isolated from the ethyl acetate-methanol extract of the brown seaweed Sargassum wightii, which represent the first example of two rare skeletal types, namely, oxo-2H-pyranyl and oxa-cyclododecadienyl macrolactone featuring the aryl substituent from marine origin. Natural bioactive food

Notes

The authors declare no competing financial interest.

Acknowledgements

This work is supported by the funding under the Science and Engineering Research Board (SERB) Scheme (SR/S1/OC-96A/2012) from Department of Science and Technology, New Delhi, India. The authors thank the Director, Central Marine Fisheries Research Institute for his valuable guidance and support. Thanks are due to the Head, Marine Biotechnology Division, Central Marine Fisheries Research Institute for facilitating the research activity.

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