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Mar. Drugs 2017, 15(5), 133; doi:10.3390/md15050133

Anti-Inflammatory Activity and Structure-Activity Relationships of Brominated Indoles from a Marine Mollusc

1
Marine Ecology Research Centre, School of Environment, Science and Engineering, Southern Cross University, G.P.O. Box 157, Lismore, NSW 2480, Australia
2
Centre for Health Sciences Research, University of Southern Queensland, Toowoomba, QLD 4350, Australia
3
Analytical Research Laboratory, Southern Cross Plant Science, Southern Cross University, G.P.O. Box 157, Lismore, NSW 2480, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Keith B. Glaser
Received: 14 March 2017 / Revised: 18 April 2017 / Accepted: 2 May 2017 / Published: 6 May 2017
(This article belongs to the Special Issue Marine Compounds and Inflammation II, 2017)
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Abstract

Marine molluscs are rich in biologically active natural products that provide new potential sources of anti-inflammatory agents. Here we used bioassay guided fractionation of extracts from the muricid Dicathais orbita to identify brominated indoles with anti-inflammatory activity, based on the inhibition of nitric oxide (NO) and tumour necrosis factor α (TNFα) in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages and prostaglandin E2 (PGE2) in calcium ionophore-stimulated 3T3 ccl-92 fibroblasts. Muricid brominated indoles were then compared to a range of synthetic indoles to determine structure-activity relationships. Both hypobranchial gland and egg extracts inhibited the production of NO significantly with IC50 of 30.8 and 40 μg/mL, respectively. The hypobranchial gland extract also inhibited the production of TNFα and PGE2 with IC50 of 43.03 µg/mL and 34.24 µg/mL, respectively. The purified mono-brominated indole and isatin compounds showed significant inhibitory activity against NO, TNFα, and PGE2, and were more active than dimer indoles and non-brominated isatin. The position of the bromine atom on the isatin benzene ring significantly affected the activity, with 5Br > 6Br > 7Br. The mode of action for the active hypobranchial gland extract, 6-bromoindole, and 6-bromoisatin was further tested by the assessment of the translocation of nuclear factor kappa B (NFκB) in LPS-stimulated RAW264.7 mouse macrophage. The extract (40 µg/mL) significantly inhibited the translocation of NFκB in the LPS-stimulated RAW264.7 macrophages by 48.2%, whereas 40 µg/mL of 6-bromoindole and 6-bromoistain caused a 60.7% and 63.7% reduction in NFκB, respectively. These results identify simple brominated indoles as useful anti-inflammatory drug leads and support the development of extracts from the Australian muricid D. orbita, as a new potential natural remedy for the treatment of inflammation. View Full-Text
Keywords: marine natural products; inflammation; NO inhibition; Muricidae; isatin; Tyrian purple marine natural products; inflammation; NO inhibition; Muricidae; isatin; Tyrian purple
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ahmad, T.B.; Rudd, D.; Smith, J.; Kotiw, M.; Mouatt, P.; Seymour, L.M.; Liu, L.; Benkendorff, K. Anti-Inflammatory Activity and Structure-Activity Relationships of Brominated Indoles from a Marine Mollusc. Mar. Drugs 2017, 15, 133.

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