Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

Abstract

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure–activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.

Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydrogenases

“…For the two most potent compounds, IC 50 values were determined. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with an IC 50 of 4.6 ± 0.8 µM and 1.3 ± 0.5 µM [ 19 ], respectively ( Figure 4 B). A mixture of ethyl- (6 µM) and hexylparaben (12 µM) showed additive effects in terms of 17β-HSD2 inhibition compared to each individual compound ( Figure 5 ).…”

“…The effect of 6 μM ethyl- (2-P) or 12 μM hexylparaben (6-P) or a mixture of both compounds on 17β-HSD2 activity was assessed in lysates of transiently-transfected HEK-293 cells. Dimethylsulfoxide (DMSO) vehicle served as a negative control and nordihydroguaiaretic acid (NDGA) as a positive control [ 19 ]. Experiments were performed three times, independently.…”

The Genus Eriosema (Fabaceae): From the Ethnopharmacology to an Evidence-Based Phytotherapeutic Perspective?

“…In line with this 17β-HSD2 is more and more considered as target for antiosteoporosis treatment. In an in vitro assay using lysates of cells expressing the recombinant human enzyme 17β-HSD2, Vuorinen et al (2017) tested 36 hit molecules, including 44 and 73 from E. laurentii. These compounds with respective IC 50 values of 1.52 and 2.03 µM were among the most active 17β-HSD2 inhibitors tested.…”

“…These compounds with respective IC 50 values of 1.52 and 2.03 µM were among the most active 17β-HSD2 inhibitors tested. However, they selectively inhibited 17β-HSD1 (that catalyzes the reverse reaction) over 17β-HSD2 and therefore cannot be suitable lead structures for a possible therapeutic use (Vuorinen et al, 2017).…”

Bioactive Molecules and Their Mechanisms of Action

“…Osteoporosis is a highly prevalent bone disease caused by an inappropriate rate of bone resorption compared with bone formation, and the characterization of novel compounds with anti-osteoporotic potential is of high interest [33,34,35,36]. Yodthong et al reported that L-quebrachitol promoted the proliferation, differentiation, and mineralization of pre-osteoblastic MC3T3-E1 cells by triggering the bone morphogenetic protein-2 (BMP-2)-response, as well as the runt-related transcription factor-2 (Runx2), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin signaling pathway [37].…”