Extracts of Peperomia pellucida [L.] Kunth have previously been demonstrated to have in vivo estrogenic-like effects, thereby functioning as an anti-osteoporotic agent. However, the compounds responsible for these effects have not yet been determined. Therefore, the aim of this study is to isolate and elucidate potential compounds with estrogenic activity. The structures of the isolated compounds were identified using 1D 1H and 13C-NMR and confirmed by 2D FT-NMR. The estrogenic activity was evaluated using the E-SCREEN assay, and a molecular docking study was performed to predict the binding affinity of the isolated compounds to estrogen receptors. In this experiment, we successfully isolated three phenylpropanoids and two lignan derivatives, namely, 6-allyl-5-methoxy-1,3-benzodioxol-4-ol (1), pachypostaudin B (2), pellucidin A (3), dillapiole (4), and apiol (5). Among these compounds, the isolation of 1 and 2 from P. pellucida is reported for the first time in this study. Activity assays clearly showed that the ethyl acetate extract and its fractions, subfractions, and isolated compounds exerted estrogenic activity. Methanol fraction of the ethyl acetate extract produced the highest estrogenic activity, while 1 and 2 had partial agonist activity. Some compounds (derivates of dillapiole and pellucidin A) also had, in addition, anti-estrogenic activity. In the docking study, the estrogenic activities of 1–5 appeared to be mediated by a classical ligand-dependent mechanism as suggested by the binding interaction between the compounds and estrogen receptors; binding occurred on Arg 394 and His 524 of the alpha receptor and Arg 346 and His 475 of the beta receptor. In summary, we reveal that P. pellucida is a promising anti-osteoporotic agent due to its estrogenic activity, and the compounds responsible for this activity were found to be lignan and phenylpropanoid derivatives. The presence of other compounds in either the extract or fraction may contribute to a synergistic effect, as suggested by the higher estrogenic activity of the methanol fraction. Hence, we suggest further research on the osteoporotic activity and safety of the identified compounds, especially regarding their effects on estrogen-responsive organs.

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Peperomia pellucida (L.) Kunth has been studied as an anti-osteoporotic agent. However, there is no report about its estrogenic activity, which is important for its anti-osteoporotic activity. Thus, the aim of this research was to study the estrogenic potency of P. pellucida extracts. The estrogenic activity of P. pellucida extracts (n-hexane, ethyl acetate, ethanol, and water extracts) was studied using E-screen assay and confirmed with a molecular docking simulations. Further, the presence of phytoestrogen compounds was identified using thin layer chromatography (TLC), TLC densitometry, and high performance liquid chromatography. The n-hexane, ethyl acetate, and ethanol extracts at a concentration of 0.1 μg mL-1 exhibited a partial agonist effect, whereas the water extract showed full agonisteffect at the similar concentration. This activity was produced through a classical ligand-dependent mechanism similar to estradiol. N-hexane and ethyl acetate extracts showed antiestrogenic activity. The TLC chromatogram evidently depicted the presence of quercetin and stigmasterol in the n-hexane and ethyl acetate extracts. Apigenin and apigetrin at concentrations of 0.239±0.076 and 1.063±0.156 μg mg-1 extract, respectively, were present in the water extract. A docking study on estrogen receptors confirmed that apigetrin prefer to produce estrogenic activity, whereas the other compounds can produce both estrogenic and antiestrogenic activity. Hence, we suggest that the bioactive compounds in the water extract are flavonoids, such as apigenin and apigetrin. In summary, the water extract is recommended to be used as an estrogenic agent.