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

ABSTRACT:

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-1?, TNF-? and IFN-?) 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-? in THP-1 macrophages together with IL-8 in SW480 cells.

Conclusions

The observed profile of cytokine modulation (IL-6/ TNF-?, 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.

SUBMITTER: Chan K 

PROVIDER: S-EPMC7497186 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature