Abstract
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.
Highlights
Selective estrogen receptor modulator (SERM) refers to a structurally diverse group of compounds that binds to both estrogen receptor subtypes estrogen receptor α (ERα) and/or ERβ despite lacking the estrogen steroid moiety
The formation of all compounds and their purity were confirmed via UPLC-electrospray ionization (ESI) MS
All synthesized compounds were tested for their relative β-galactosidase activity in a yeast estrogen screen (YES) assay at a concentration of 1 μM using DMSO as control
Summary
The effect ofeffect this modification analogs can bypass para-hydroxylation by polymorphic The of this modi-on the compounds estrogenic/anti-estrogenic properties is investigated. We decided to test the novel compounds in an organ-specific in vitro model using the human Ishikawa endometrial adenocarcinoma cell line [19,20]. Compounds showing appreciable estrogenic activity in the YES assay and that were able to inhibit the growth of MCF-7 cancer cell lines yet with low estrogenic activity on Ishikawa endometrial adenocarcinoma cells might serve as potential ideal SERMS. The model investigates the full agonistic activity of compound 3 despite the lack of an OH group on ring C This group was reported to be essential for ER binding affinity of most synthetic ER ligands
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