Isoguaiacins, Arylnaphthalene Types Identified as Novel Potent Estrogenic Signaling Molecules from Larrea nitida

Two isoguaiacins, arylnaphthalene type compounds 1 and 2, were isolated from Larrea nitida. Their structures were evaluated by ER binding and ERE transcription assay. In our study on the biological activities of isoguaiacins, we demonstrated lignans with a rigid structure from Larrea nitida as selective estrogen receptor modulators (SERMs). Estrogenic activity‐guided isolation of the L. nitida extract led to the identification of four lignans compounds. All four lignans displayed high binding affinity for human estrogen receptor (hER) α and β as well as transcriptional activities for estrogen response element (ERE). Furthermore, arylnaphthalene type lignans 1 (5,6,7,8‐tetrahydro‐5‐(3,4‐dihydroxyphenyl)‐6,7‐dimethylnaphthalene‐2,3‐diol) and 2 (5,6,7,8‐tetrahydro‐5‐(4‐hydroxy‐3‐methoxyphenyl)‐6,7‐dimethylnaphthalene‐2,3‐diol) showed especially high potencies for ERβ and ERE with IC50 of 0.045 and 0.85 μM, respectively. Arylnaphthalene type lignans 1 and 2 and bibenzyl butane type lignans 3 (4‐(4‐(4‐hydroxyphenyl)‐2,3‐dimethylbutyl) benzene‐1,2‐diol) increased the proliferation of MCF‐7 cells and the ERα target gene pS2 . Our results indicate that the four active lignans have selective affinities for hERβ and exhibit SERM properties. For the first time, we have discovered the estrogenic activities of isoguaiacins from L. nitida, which are promising candidates for the treatment of estrogen‐related conditions and warrant further preclinical evaluation.