Design and synthesis of glycyrrhetinic acid glycosides against acute lung injury and pulmonary fibrosis.

Abstract

HMGB1 mediated signalling pathway plays an important role in acute injury and fibrosis in lung tissues. Glycyrrhizic acid (GL) is a HMGB1 inhibitor, and its aglycone (glycyrrhetinic acid, GA) is the major pharmacophore and plays the main role during binding to HMGB1. To improve selectivity for these lung diseases, a series of novel glycyrrhetinic acid glycosides targeting mannose acceptors in the respiratory tract and lung tissues were synthesised, and their biological activities were evaluated in vitro and in vivo. For normal lung cell lines WI-38 and Beas-2B, all the compounds but c6 showed reduced cytotoxicity vs the positive controls (GA and GL), IC₅₀ values were > 800 µM. For three cancer cells, c1 exhibited high selectivity for lung cancer cells A549. In the inflammation assays, compound c1 displayed the strongest activity of NO inhibition, and c4 was next; both them not only down-regulated the expression levels of IL-1β and TNF-α in RAW264.7 cells, but also decreased the levels of TNF-α, IL-1β, HMGB1, RAGE and ROS in A549 cells in a dose-dependent manner. Noteworthy, compound c1 of 50 μM reduced the levels of HMGB1 and RAGE to 38.4 and 37.0% of the LPS group, and it showed much higher binding affinity with HMGB1 than GL, which confirmed by molecular docking; in addition, c1 also inhibited the deposition of α-SMA and Col-1 proteins in TGF-β1-activated A549 cells. In the bleomycin-induced lung fibrosis mouse model, c1 decreased fibrous protein production and deposition in the lung tissues; at a 30 mg/kg dose, it reduced the levels of α-SMA and Col-1 to 48.12 and 56.37% of the BLM group, respectively. The pharmacokinetics tests showed c1 relative distribution rate in lung tissue (at 1 h, 18.86%; at 2 h, 12.80%) is much higher than that of GA (at 1 h, 2.8%; at 2 h, 1.9%). These results show compound c1 is likely to be a candidate for acute lung injury and pulmonary fibrosis.