期刊
JOURNAL OF PHARMACY AND PHARMACOLOGY
卷 72, 期 7, 页码 927-937出版社
OXFORD UNIV PRESS
DOI: 10.1111/jphp.13269
关键词
colitis; cytokine profiling; inflammatory bowel disease; indanes; lipoxygenase; nitric oxide
资金
- Wellcome Trust [067033/Z/02/A]
- Enterprise Ireland
- Trino Therapeutics Ltd.
- Trinity College Dublin postgraduate scholarship [1252]
Objectives PH46A (1) demonstrates significant anti-inflammatory activity in phenotypic models but its mechanism and site of action have been elusive. Current study focused on the bioactivity of PH46 (2) and related novel indane dimers (6-10) to investigate the impact of changes in substitution and stereochemistry at the C-1 and C-2 positions of the PH46 (2) scaffold. Methods Cytotoxicity profiles of compounds were established using THP-1 macrophages and SW480 cells. Effects of the compounds were then evaluated at 10 mu m using 5-lipoxygenase (LOX) and 15-LOX enzymes, and 5-LOX binding was evaluated in silico against NDGA, nitric oxide (NO) released from LPS-induced SW480 cells and cytokines in THP-1 macrophages (IL-6, IL-1 beta, TNF-alpha and IFN-gamma) and in SW480 cells (IL-8). Key findings PH46 (2) and 7 cause reduction in NO, inhibition of 5-LOX with high binding energy and no cytotoxicity effects in THP-1 macrophages and SW480 cell lines (up to 50 mu m). The cytokine profiling of the series demonstrated inhibition of IL-6 and TNF-alpha in THP-1 macrophages together with IL-8 in SW480 cells. Conclusions The observed profile of cytokine modulation (IL-6/ TNF-alpha, IL-8) and inhibition of release of NO and 5-LOX may contribute to the in vivo effects demonstrated by indane dimers and PH46A (1) in murine models of colitis.
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