2’, 3’, 4’-trihydroxychalcone is an Estrogen Receptor Ligand Which Modulates the Activity of 17β-estradiol

Abstract

Menopausal hormone therapy (MHT) reduces the risk of osteoporosis, fractures, obesity and diabetes, but longterm MHT increases risk of other diseases. Safe long-term MHT that exploits its benefits and abrogates its adverse effects requires a new approach. Here we demonstrate that 2', 3', 4'-trihydroxychalcone (CC7) acts as an estrogen receptor alpha (ERα) ligand that may improve the safety profile of MHT. CC7 reprograms the actions of estradiol (E2) to regulate unique genes in bone-derived U2OS cells, with 824/1358 genes not regulated by E2. The proliferative action of E2 on human MCF-7 breast cancer cells and mouse uterus is blocked when combined with CC7. Thermostability and molecular dynamics simulation studies suggest that CC7 binds concurrently with E2 in the ERα ligand binding pocket to produce a unique coliganded conformation to modulate ERα. Compounds such as CC7 that act as coligands represent a new class of ERα reprograming drugs that potentially can be combined with existing estrogens to produce a safer MHT regimen for long-term therapy. RESULTS CC7 acts as an ER coagonist in U2OS cellsPreviously, we isolated the flavanone liquiritigenin from

Chalcones: Synthetic Chemistry Follows Where Nature Leads

“…In silico studies performed with the chalcone 2′,4′dihydroxy-6-methoxy-3,5-dimethylchalcone (44) (Figure 9), a component of the leaves of Eugenia aquea established its interaction with estrogen receptor α [45,46]. Another similar virtual screening of 2′,3′,4′-trihydroxychalcone (45) showed that this chalcone acted as an estrogen receptor ligand that could modulate the activity of 17β-estradiol [47]. 43), was proposed as useful against prostate cancer as it was noted to cause cell cycle arrest and apoptosis (Figure 7) [43].…”

“…In silico studies performed with the chalcone 2 ,4dihydroxy-6-methoxy-3,5-dimethylchalcone (44) (Figure 9), a component of the leaves of Eugenia aquea established its interaction with estrogen receptor α [45,46]. Another similar virtual screening of 2 ,3 ,4 -trihydroxychalcone (45) showed that this chalcone acted as an estrogen receptor ligand that could modulate the activity of 17β-estradiol [47]. Branham et al [48] used the estrogen receptor-ligand binding assay to assess the relative binding affinity of five chalcones, i.e., chalcone (1), 4-hydroxychalcone (20), 4′-hydroxychalcone (21), phloretin (23), and 4,2′,4′-trihydroxychalcone (46), and a significant level of binding with the estrogen receptor α was observed with all these chalcones.…”

“…Several chalcone-phenylpyran-2-one derivatives bearing a N,N-dimethyl ethylamine side chain, for example, chalcone 47, were synthesized as estrogen receptor modulators [49]. All synthesized chalcone derivatives showed selectivity toward estrogen receptor α, and among the compounds, the derivative with 2,6-dichloro functionalities (47) showed the strongest affinity toward the receptor.…”