Bioactive indanes: insight into the bioactivity of indane dimers related to the lead anti-inflammatory molecule PH46A.

Autor: Chan K; School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin 2, Ireland., Frankish N; School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin 2, Ireland., Zhang T; School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin 2, Ireland.; School of Food Science and Environmental Health, Technological University Dublin, Dublin 1, Ireland., Ece A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Topkapi-Istanbul, Turkey., Cannon A; Department of Surgery, School of Medicine, Trinity Translation Medicine Institute (TTMI), St James's Hospital, Dublin 8, Ireland., O'Sullivan J; Department of Surgery, School of Medicine, Trinity Translation Medicine Institute (TTMI), St James's Hospital, Dublin 8, Ireland., Sheridan H; School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin 2, Ireland.
Jazyk: angličtina
Zdroj: The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2020 Jul; Vol. 72 (7), pp. 927-937. Date of Electronic Publication: 2020 Apr 16.
DOI: 10.1111/jphp.13269
Abstrakt: 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 µm 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-1β, TNF-α and IFN-γ) 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 µm). The cytokine profiling of the series demonstrated inhibition of IL-6 and TNF-α in THP-1 macrophages together with IL-8 in SW480 cells.
Conclusions: The observed profile of cytokine modulation (IL-6/ TNF-α, 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.
(© 2020 Royal Pharmaceutical Society.)
Databáze: MEDLINE
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