Structurally Diverse Labdane Diterpenoids from Leonurus japonicus and Their Anti-inflammatory Properties in LPS-Induced RAW264.7 Cells

Abstract

A phytochemical study on the aerial parts of Leonurus japonicus led to the isolation and identification of 38 labdane diterpenoids, including 18 new (1, 2, 11, 12, 16–21, 24, 30–34, 37, 38) and 20 known (3–10, 13–15, 22, 23, 25–29, 35, 36) analogues. Their structures were elucidated based on physical data analysis, including 1D and 2D NMR, HRMS, UV, IR, and X-ray diffraction. The structure of the known compound 4 was confirmed by single-crystal X-ray diffraction data. These compounds can be divided into furanolabdane (1–10), tetrahydro­furanolabdane (11–15), lactonelabdane (16–23), labdane (24–29), and seco-labdane (30–38) type diterpenoids. All compounds were screened by lipopolysaccharide (LPS)-induced nitric acid (NO) production in RAW264.7 cells to evaluate anti-inflammatory effects. Compounds 1, 5, 10–13, 16–19, 31–33, and 38 inhibited NO production with IC50 values lower than 50 μM, with compound 30 being the most active, with an IC50 value of 3.9 ± 1.7 μM. Further studies show that compound 30 inhibits pro-inflammatory cytokine production and IKK α/β phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.

seco‐Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C−C Bond Cleavage

“…Niemeyer and co‐workers reported the isolation of 5,5‐spiroketal containing 8,9‐ seco ‐labdanes 95 – 96 from H. parvifolius in 1991 (Figure 6). [87] Persianone ( 97 ) was isolated from Ballota aucheri in 1995, Leonurus sibiricus in 2014 and Leonurus japonicus in 2015 and 2020 [88–91] . Persianone ( 97 ) contains a similar ketal motif to 95 – 96 , and was shown to inhibit human liver cytosol estrogen sulfotransferase (E‐ST), an enzyme that is involved in the maintenance of cellular estrogen levels [88–90] …”

“…These include 107 , 108 and 109 from L. japonicus as well as 110 from L. sibiricus [89, 90] . In 2020, Xiao and co‐workers reported the isolation of a further 38 labdanes from L. japonicus , including seven previously unreported seco ‐labdanes, 111 – 117 , and two known seco ‐labdanes, persianone ( 97 ) and 108 [91] . All the labdanes were screened for anti‐inflammatory activity by lipopolysaccharide (LPS)‐induced nitric acid (NO) production in RAW264.7 cells.…”

“…All the labdanes were screened for anti‐inflammatory activity by lipopolysaccharide (LPS)‐induced nitric acid (NO) production in RAW264.7 cells. Interestingly, seco ‐labdane 114 was found to be the most active (IC 50 3.9±1.7 μ m ) and further investigation showed that it inhibits pro‐inflammatory cytokine production and IKK α/β phosphorylation, and acts to restore IκB expression levels in NF‐κB signalling pathways [91] …”

Preliminary Evaluation of Wound Healing Potential of Leonurus japonicus Houtt. Extracts

“…[16,17] Also, the aerial parts of the plant are used to treat bruises and other inflammatory conditions. [18][19][20][21] These uses are due to anti-inflammatory, antioxidant, and antibacterial properties related to secondary metabolites, like polyphenolic compounds, present in this species and described in some phytochemical studies. [10,22,23] Despite some research describing the anti-inflammatory potential of this vegetal species and identifying the chemical compounds, no study has been published investigating the effect of extracts of L. japonicus on the wound healing process and correlating this effect with the secondary metabolites present in these extracts.…”

Comparative genomic analysis betweenLeonurus japonicusandLeonurus sibiricus

“…The authoritative book on Traditional Chinese Medicine, Ben Cao Gang Mu described it as a “panacea in treating diseases about blood” (Miao et al, 2019). Modern pharmacological studies have shown that L. japonicus has effects on the uterus as well as cardioprotective (Chen et al, 2017), anti-inflammatory (Li et al, 2020a; Yang et al, 2020; Zhang et al, 2020), hepatoprotective (Tian et al, 2021), antioxidative (Liao et al, 2021), antitumour (Park et al, 2022; Yue et al, 2020), angiogenic (He et al, 2018; Zhou et al, 2020), neuroprotective (Li et al, 2020b) and antibacterial activities (Xiong et al, 2013).…”