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

• Published in: International journal of molecular sciences Vol. 22; no. 22; p. 12575
• Main Authors: Elnakib, Heba E, Ramsis, Marian M, Albably, Nouran O, Vector, Merna A, Weigand, Jan J, Schwedtmann, Kai, Wober, Jannette, Zierau, Oliver, Vollmer, Günter, Abadi, Ashraf H, Ahmed, Nermin S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.11.2021; MDPI
• Subjects: Adenocarcinoma; Alkaline phosphatase; Analogs; Animals; Antiestrogens; Assaying; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cardiovascular disease; Chlorine; CYP2D6; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrium; Enzymes; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogenic activity; Estrogens; Female; Fluorine; Humans; Hyperplasia; Ishikawa cells; MCF-7; MCF-7 Cells; Metabolism; Metabolites; Metastases; Metastasis; Ovariectomy; Piperidine; Rats; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - genetics; Selective estrogen receptor modulators; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - pharmacology; SERM; Stilbenes - chemical synthesis; Stilbenes - pharmacology; tamoxifen; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; TNBC; Triphenylethylene; Tumor cell lines; Uterus; Xenoestrogens; Yeast; uterotrophic; CYP2D6; Ishikawa cells; MCF-7; SERM; TNBC; tamoxifen
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222212575

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 , and 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 ( -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 GI = 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 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 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.