Anti-inflammatory activity and structure-activity relationships of brominated indoles from a marine mollusc

Tarek B. Ahmad, David Rudd, Joshua Smith, Michael Kotiw, Peter Mouatt, Lisa M. Seymour, Lei Liu, Kirsten Benkendorff

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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.

Original languageEnglish
Article number133
Number of pages19
JournalMarine Drugs
Volume15
Issue number5
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

Keywords

  • Inflammation
  • Isatin
  • Marine natural products
  • Muricidae
  • NO inhibition
  • Tyrian purple

Cite this

Ahmad, T. B., Rudd, D., Smith, J., Kotiw, M., Mouatt, P., Seymour, L. M., Liu, L., & Benkendorff, K. (2017). Anti-inflammatory activity and structure-activity relationships of brominated indoles from a marine mollusc. Marine Drugs, 15(5), [133]. https://doi.org/10.3390/md15050133