Involvement of the Glucocorticoid Receptor in Pro-inflammatory Transcription Factor Inhibition by Daucane Esters from <i>Laserpitium zernyi</i>

Species of the genus <i>Laserpitium</i> have been used traditionally to treat inflammation and infection. From the herb of <i>Laserpitium zernyi</i>, six new compounds were isolated and their structures elucidated (using IR, NMR, HRMS data) as derivatives of 8-daucene-2,4,10-triol (<b>1</b>, <b>2</b>, and <b>4</b>), 7-daucene-2,4,10-triol (<b>3</b>), a lapiferin derivative featuring a C-2 ester moiety (<b>5</b>), and a daucane featuring an exomethylene group at C-8 (<b>6</b>). Also isolated were the rare daucanes vaginatin (<b>7</b>) and laserpitin (<b>8</b>). In a search for selective glucocorticoid receptor (GR) modulators, the compounds were tested for their capacity to inhibit NF-κB and AP-1 pro-inflammatory factors and for a potential competitive effect on a dexamethasone (Dex)-induced GR-driven glucocorticoid response element (GRE) reporter gene. The new 2β-angeloyloxy-10α-acetoxy-8-daucene-2,4,10-triol (<b>2</b>) significantly inhibited transactivation of both NF-κB and AP-1, while vaginatin (<b>7</b>) was the most active of the compounds tested in blocking AP-1. Both compounds competitively repressed Dex-induced GRE-driven promoter activities, indicative of a potential role for GR. In addition, a decreased potential to inhibit NF-κB was apparent in GR knockout A549 cells. In line with the transcriptional assays, compounds <b>2</b> and <b>7</b> also significantly lowered CCL-2 chemokine production, albeit to a lesser extent than Dex. The results suggest that daucanes may be interesting candidates in the search for compounds with GR-modulating activities.