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

Ahmad, Tarek B. and Rudd, David and Smith, Joshua and Kotiw, Michael and Mouatt, Peter and Seymour, Lisa M. and Liu, Lei and Benkendorff, Kirsten (2017) Anti-inflammatory activity and structure-activity relationships of brominated indoles from a marine mollusc. Marine Drugs, 15 (5). pp. 133-151.

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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 (TNF) 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 ug/mL, respectively. The hypobranchial gland extract also inhibited the production of TNFa and PGE2 with IC50 of 43.03 ug/mL and 34.24 ug/mL, respectively. The purified mono-brominated indole and isatin compounds showed
significant inhibitory activity against NO, TNFa, 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 (NFkB) in LPS-stimulated RAW264.7 mouse macrophage. The extract
(40 ug/mL) significantly inhibited the translocation of NFkB in the LPS-stimulated RAW264.7 macrophages by 48.2%, whereas 40 ug/mL of 6-bromoindole and 6-bromoistain caused a 60.7% and 63.7% reduction in NFkB, 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.

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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Published version made available under Open Access.
Faculty/School / Institute/Centre: No Faculty
Faculty/School / Institute/Centre: No Faculty
Date Deposited: 26 Oct 2017 00:00
Last Modified: 31 Aug 2018 01:46
Uncontrolled Keywords: marine natural products; inflammation; NO inhibition; Muricidae; isatin; Tyrian purple
Fields of Research (2008): 11 Medical and Health Sciences > 1104 Complementary and Alternative Medicine > 110499 Complementary and Alternative Medicine not elsewhere classified
Socio-Economic Objectives (2008): C Society > 92 Health > 9202 Health and Support Services > 920201 Allied Health Therapies (excl. Mental Health Services)
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