Novel benzofuran derivative DK-1014 attenuates lung inflammation via blocking of MAPK/AP-1 and AKT/mTOR signaling in vitro and in vivo

Xuezhen Xu,Yourim Lim,Sei-Ryang Oh,Ok-Kyoung Kwon,Hye-Gwang Jeong,In-Sik Shin,Kyeong Lee,Qili Lu,Jyotirling R Mali,Dipesh S Harmalkar,Kyung-Seop Ahn,Gilhye Lee

doi:10.1038/s41598-018-36925-9

Abstract

Benzofuran derivatives have wide range of biological activities as anti-oxidant, anti-inflammatory and anticonvulsant agent. In this study, we investigated whether the novel benzofuran derivative, DK-1014 has the anti-inflammatory effects on macrophage and lung epithelial cells and anti-asthmatic effects on ovalbumin-treated mice. A series of 2-arylbenzofuran analogues were synthesized and evaluated for NO and interleukin-6 (IL-6) inhibition in LPS-stimulated Raw264.7 cells. Of these analogues, compounds 8, 22a, 22d, and 22 f (DK-1014) exhibited notable inhibitory activity with respect to IL-6 and NO production. In particular, compound DK-1014 strongly reduced IL-6, IL-8, and MMP-9 mRNA expression and IL-6, IL-8, and MCP-1 production in phorbol myristate acetate stimulated A549 cells, reduced MAPKs phosphorylation and c-fos translocation, and attenuated AKT, p70S6K and GSK phosphorylation. In vivo experiments were also performed on ovalbumin-sensitized and challenged BALB/c mice. DK-1014 reduced the airway hyperresponsiveness, inflammatory cell counts and cytokine levels (IL-4, 5, 13) in bronchial alveolar lavage fluid (BALF) and immunoglobulin E in serum, and attenuated inflammatory cell infiltration and mucus hypersecretion in lung tissue. These findings indicate that DK-1014 can protect against allergic airway inflammation through the AP-1 and AKT/mTOR pathways and could be useful source for the development of a therapeutic agent for asthma.

Highlights

Recent studies have proposed MMPs as important inflammation regulators[11]
Considering the multifarious potential applications of homoegonol for development of anti-inflammatory agent, we report in this study synthesis and structure-activity relationship of a series of homoegonol analogues with 2-arylbenzofuran scaffolds and in vitro assays of IL-6 and NO production inhibitory activity in Raw264.7 cells
Many approaches to the synthesis of homoegonol have been reported[24,25,26,27,28], with most based on the construction of a benzofuran backbone using the Sonogashira coupling of O-halophenols with a palladium catalyst, e.g. PdCl2(PPh3)[224]

Summary

Introduction

Recent studies have proposed MMPs (matrix metalloproteinase) as important inflammation regulators[11]. PI3K activates the AKT serine/threonine kinase pathway via direct TSC2 phosphorylation. Recent studies have found that several pan PI3K inhibitors, including LY294002 and mTOR inhibitor rapamycin, attenuate allergic airway inflammation by suppressing mTOR and p70S6K phosphorylation in mice that have inhaled ovalbumin (OVA)[19]. Considering the multifarious potential applications of homoegonol for development of anti-inflammatory agent, we report in this study synthesis and structure-activity relationship of a series of homoegonol analogues with 2-arylbenzofuran scaffolds and in vitro assays of IL-6 and NO production inhibitory activity in Raw264.7 cells. The novel 2-arylbenzofuran analogue DK-1014 is demonstrated to have protective effects against the inflammation of human lung epithelial cells and in asthmatic mice, making it a interesting candidate for the treatment of inflammatory disease

Methods

Results

Conclusion