Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS; a syndrome comprising acute hypoxemic respiratory failure with bilateral pulmonary infiltrates) are characterized by diffuse alveolar damage, pulmonary edema, hypoxemia, and edema. These features lead to severe inflammation [1,2]. The mortality associated with ALI is high (40%) [3]. Systemic and direct lung injury can initiate ALI and ARDS, but the expansion of inflammatory responses is responsible for injury progression. Macrophages are deeply involved in ALI development following infection and exposure to noninfectious stimuli because they produce proinflammatory cytokines [4,5]. Various proinflammatory cytokines are secreted by infiltrating macrophages. Among these cytokines, those that promote the inflammatory cascade are considered to be proinflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, chemokines, and the interferon family. Cytokines contribute most to the deterioration seen in ALI [6]. In addition, increased levels of IL-6, IL-1β, and TNF-α have been found in experimental ALI [[7], [8], [9], [10]].

Nitric oxide (NO) can also cause vasodilation and tissue damage in inflammatory sites. NO plays a key part in inflammatory responses [11]. Acute inflammation is the leading cause of ALI, and the prevalence of hospitalization of patients with ALI is increasing. Therefore, anti-inflammatory treatment has emerged as a reasonable approach to manage ALI [12]. The need to develop drugs that inhibit the production and release of proinflammatory cytokines for ALI treatment is urgent.

Specific drugs to treat ALI are lacking. Due to certain issues (e.g., drug resistance and toxicity), drug-based treatment for ALI is also extremely limited. Drug candidates have entered certain stages (clinical research, preclinical research, and bioactivity evaluation), but it will be a long time before drugs are approved for marketing [[13], [14], [15], [16], [17], [18]]. Therefore, new, efficacious, and safe anti-inflammatory drugs with new structural frameworks are needed to inhibit the release of proinflammatory cytokines for treating inflammatory-related diseases such as ALI [[19], [20], [21]].

In recent years, active products isolated from various natural resources have played an important part in drug development. Great efforts have been made to discover lead compounds from natural products to obtain new anti-inflammatory agents.

9′-O-di-(E)-feruloyl-meso-5,5′-dimethoxysecoisolariciresinol (LCA) is a naturally abundant dibenzylbutane lignan isolated from the roots of Litsea cubeba (Lour.) Pers. LCA has been used for centuries in traditional China medicine formulations for the treatment of rheumatic diseases. LCA has been demonstrated to have anti-inflammatory effects. It has been shown to exert anti-osteoarthritic activity by inhibiting lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in RAW 264.7 cells [22]. LPS stimulates RAW 264.7 cells to secrete proinflammatory factors such as NO, IL-1β, IL-6, and TNF-α. Overproduction of NO and proinflammatory factors is closely associated with inflammatory diseases [[23], [24], [25], [26]].

After comprehensive analyses of the natural structure of LCA, we performed a trans-synthetic analysis and asymmetric total synthesis. On the basis of total synthesis, we obtained LCA derivatives through rational design strategies (e.g., the ability to form hydrogen bonds in docking, and compound stability). Additional screening was performed to obtain the corresponding anti-inflammatory compounds. Preliminary conclusions on the structure–activity relationship (SAR) were made. Then, the potential mechanism of action of the selected compound was investigated.

We designed and synthesized 33 LCA derivatives. Then, we evaluated the inhibitory effect of these derivatives on the release of NO and proinflammatory cytokines in vitro. Among them, 14r exhibited the best inhibitory effect and could inhibit activation of the nuclear factor-kappa B (NF-κB) pathway. Moreover, 14r could improve the symptoms of LPS-induced ALI in vivo.