Acute
lung injury (ALI) is often caused by systemic inflammatory
responses. Targeting the myeloid differentiation protein 2/toll-like
receptor 4 (MD2–TLR4) complex may be a promising way to treat
Gram-negative bacterial-induced inflammatory disorders. In this study,
we report the design and synthesis of a new series of 3-(indol-5-yl)-indazoles,
which were evaluated for their anti-inflammatory activities in macrophages.
Among the analogues generated, the promising 3-(indol-5-yl)-indazole
analogue 22m inhibited lipopolysaccharide (LPS)-induced
expression of tumor necrosis factor alpha (TNF-α) and interleukin-6
(IL-6) in macrophages with IC50 values of 0.89 and 0.53
μM, respectively. Compound 22m was then identified
as an MD2–TLR4 antagonist in suppressing LPS-induced inflammatory
responses. In vivo administration of 22m significantly
inhibited macrophage infiltration and ameliorated histopathological
changes in lung tissues of LPS-challenged mice. Our studies have identified
a new 3-(indol-5-yl)-indazole, 22m, as a potent MD2–TLR4
inhibitor and lay the groundwork for future drug development of anti-inflammatory
agents for the treatment of ALI.
The known chalcone (±)-sanjuanolide (1) can be isolated from Dalea f rutescens. This study presents a convergent strategy for the first total synthesis of (R)-, (S)-, and (±)-sanjuanolide (1). The key step for synthesizing (R)-and (S)-1 was a Corey−Bakshi−Shibata enantioselective carbonyl reduction to construct the C-2″ configuration. (R)-1 efficiently inhibited the lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), while (S)-1 produced no significant anti-inflammatory effect. (R)-1 also effectively inhibited the mRNA expression of several inflammatory cytokines after the LPS challenge in vitro. The synthesis and biological properties of these compounds have confirmed (R)-sanjuanolide and (±)-sanjuanolide as promising new leads for developing anti-inflammatory agents.
Acute lung injury (ALI) has a high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[3,2-a]pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti-inflammatory activities. Structure-activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS-induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2-a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI.
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