Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

Abstract

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Herein we report novel TAM analogues that can avoid metabolism via CYP2D6. The novel analogues bear a flexible skeleton. Compounds have either an ester group on ring C or homodiaminoalkoxy groups on rings B and C.propenyl]phenol) was found to be ten-fold more potent than TAM on MCF-7 cells (GI 50 = 0.15 μM). It showed fivefold greater inhibitory activity on MDA-MB-231 cells than TAM (GI 50 = 1.71 μM). Compound 13 (4-{3,3-bis-[4-(3dimethylaminopropoxy)phenyl]-2-methylallyl}methoxybenzene) was the most potent among the homodiaminoalkoxy derivatives (GI 50 = 0.44) on both MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, the COMPARE algorithm suggested that it has different molecular targets from those of some other reported anticancer drugs.

Design, synthesis, and in‐silico study of novel triarylethylene analogs with dual anti‐estrogenic and serotonergic activity

“…The in vitro results indicate that we have successfully prepared significantly potent TAM analogs, our previous results confirmed the ability of similar analogs to bypass CYP2D6 metabolism (Ahmed et al, 2016; Ahmed & Wober, 2020; Elbagoury et al, 2023; Elghazawy et al, 2016; Hassan et al, 2022). Additionally, some of the novel compounds showed higher potency in inhibiting growth of ER+ and ER− BC cell lines compared to TAM.…”

“…Monoalkylated and dialkylated ether products were formed in a ratio of 1:1. Separation using silica gel column chromatographic was performed to provide the monoalkylated derivatives ( 2‐8 ) as a mixture of E–Z isomers (Elbagoury et al, 2023; Hassan et al, 2022). Ultimately, the decision to pursue stereospecific synthesis of a compound depends on its specific target interactions and since we had no previous data on the isomer that would preferably bind to 5‐HT receptors, we opted for obtaining the two isomers.…”

“…Compounds 2–8 bearing a hydroxyl group on ring C and different aminoalkoxy side chains on ring B , compounds 4 and 8 were the most anti‐estrogenic compounds with relative β‐galactosidase activity of 0.42 and 0.18, respectively. We previously reported the SAR of this series of compounds except for compound 3 (Ahmed & Wober, 2020; Hassan et al, 2022). It is worth mentioning that compound 8 was the only compound that showed equipotent activity to 4‐OH‐TAM.…”

“…The final product was further purified using chromatography to give compounds (2-8). Except for compound 3, compounds 2-8 were previously reported by our research group (Hassan et al, 2022).…”

“…Some of those compounds were more potent on both MCF‐7 and MDA‐MB231 compared to TAM. The in‐silico results showed that the compounds adopted an antagonistic configuration, and the carbamate group were involved in two essential interactions with ER‐LBD namely E353 and R394 (Ahmed et al, 2016; Ahmed & Wober, 2020; Elbagoury et al, 2023; Elghazawy et al, 2016; Hassan et al, 2022).…”