Andrographolide analogues are agonists of the estrogen receptor alpha in vitro and in vivo.

Estrogen mediates diverse physiological and pathological processes through estrogen receptors (ERα and ERβ). Andrographolide analogues have broad pharmacological effects including anti-inflammation and antimicrobial, antiviral, and hepatoprotective activity. However, the direct targets of these andrographolide analogues are not clear yet. To evaluate whether andrographolide analogues deoxyandrographolide (DAGP), 14-deoxyandrographolide (14-DAGP) and 14-deoxy-11, 12-didehydroandrographolide (DDHA) could activate ERs, computational molecular docking, surface plasmon resonance (SPR) using purified ERα and ERβ ligand binding domain (LBD) proteins, luciferase reporter assay, and in vivo animal experiments were conducted. Molecular docking and SPR confirmed direct interaction of these analogues with ERα/β LBD. 14-DAGP and DDHA activated ERα (not ERβ) transcriptional activity in reporter assays, and stimulated endometrial cell proliferation in ovariectomized female mice and rats, indicating ERα agonism in vivo. 14-DAGP decreased total white adipose tissue (WAT) mass in ovariectomized rodents by activating ERα. In male mice, DDHA reduced UV-induced skin damage via ERα activation. This study identifies andrographolide analogues 14-DAGP and DDHA as a class of phytoestrogens in vitro and in vivo. They could reduce WAT mass and alleviate UV-induced skin damage in vivo through activation of ERα. Further studies are merited to reveal whether ERα mediated other pharmacological activities of andrographolide analogues.