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1.4 CHEMICAL SCIENCES, 1.6 BIOLOGICAL SCIENCES, 3. MEDICAL AND HEALTH SCIENCES
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-1b, TNF-a and IFN-c) 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-a in THP-1 macrophages together with IL-8 in SW480 cells.
Conclusions The observed profile of cytokine modulation (IL-6/ TNF-a, 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.
Chan, K., Frankish, N., Zhang, T., Ece, A., Cannon, A., O'Sullivan, J. and Sheridan, H. (2020). Bioactive indanes: insight into the bioactivity of indane dimers related to the lead anti‐inflammatory molecule PH46A.Journal of Pharmacy and Pharmacology. doi:10.1111/jphp.13269