Total synthesis of a novel C9-monoterpenoid alkaloid, Forsyqinlingine C, and its therapeutic potential in sepsis-induced acute lung injury via modulation of the TLR4/TRIF/NF-κB pathway.

Sepsis-induced acute lung injury (ALI) is a critical health concern with high morbidity and mortality, while its effective treatment options are limited. Our previous study, identified forsyqinlingine C (FC), a novel C9-monoterpenoid alkaloid from the ripe fruit of Forsythia suspensa (Thunb.) Vahl, exhibits notable anti-inflammatory activity. In this study, we reported the total synthesis of FC and its therapeutic potential against sepsis-induced ALI for the first time. The target compound was achieved in four steps, including barbier reaction, heck reaction, hydroxyl reduction and hydroboration oxidation, with impressive combined yields of 45 % and high purity of 95 %. In biological study, an inflammatory cell model and a murine model of sepsis-induced ALI were established to explore the potential protective effect of FC and its underlying mechanisms. Our findings indicated that FC could inhibit the expression levels of TLR4, TRIF, p-NF-κB p65, and p-IκB-α and reduce the production of downstream inflammatory cytokine (IL-6 and TNF-α) in MLE-12 cells. In vivo, FC significantly alleviates LPS-induced lung injury by reducing MPO levels, and lung W/D ratios, and ameliorating histopathological alterations. FC also decreased TNF-α and IL-6 production induced by LPS in the murine serum, BALF, and lung tissue in a dose-dependent manner. Meanwhile, FC inhibited the expression levels of TLR4, TRIF, p-NF-κB p65, and p-IκB-α, which are activated by LPS administration. Furthermore, molecular docking studies results speculated that FC could disturb the TLR4/TRIF signaling pathway. In conclusion, FC demonstrated potential in alleviating sepsis-induced ALI, primarily by inhibiting LPS-stimulated inflammatory response through the TLR4/TRIF/NF-κB signaling pathway. This research offers an alternative treatment for sepsis-induced ALI.