Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung



Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues.


FachzeitschriftInternational journal of molecular sciences
PublikationsstatusVeröffentlicht - 22 Nov. 2021

Externe IDs

PubMedCentral PMC8621172
Scopus 85119411943
ORCID /0000-0001-5397-7972/work/142245261
ORCID /0000-0001-7323-7816/work/142257414


Ziele für nachhaltige Entwicklung


  • Animals, Breast Neoplasms/drug therapy, Endometrial Neoplasms/drug therapy, Estrogen Antagonists/chemical synthesis, Estrogen Receptor alpha/genetics, Female, Humans, MCF-7 Cells, Rats, Receptors, Estrogen/antagonists & inhibitors, Selective Estrogen Receptor Modulators/chemical synthesis, Stilbenes/chemical synthesis, Tamoxifen/analogs & derivatives