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

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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Heba E. Elnakib, Marian M. Ramsis, Nouran O. Albably, Merna A. Vector, Jan J. Weigand, Kai Schwedtmann, Jannette Wober, Oliver Zierau, Günter Vollmer, Ashraf H. Abadi, Nermin S. Ahmed
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tamoxifen CYP2D6 MCF-7 Ishikawa cells SERM TNBC Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/02806fab66f74a54bdf6c60bef1b845b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:02806fab66f74a54bdf6c60bef1b845b
record_format	dspace
spelling	oai:doaj.org-article:02806fab66f74a54bdf6c60bef1b845b2021-11-25T17:58:00ZManipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs10.3390/ijms2222125751422-00671661-6596https://doaj.org/article/02806fab66f74a54bdf6c60bef1b845b2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12575https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Selective 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 <b>A</b>, <b>B,</b> and <b>C</b> 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 <b>12</b> (<i>E/Z</i>-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<sub>50</sub> = 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 <b>12</b> 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 <b>12</b> 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.Heba E. ElnakibMarian M. RamsisNouran O. AlbablyMerna A. VectorJan J. WeigandKai SchwedtmannJannette WoberOliver ZierauGünter VollmerAshraf H. AbadiNermin S. AhmedMDPI AGarticletamoxifenCYP2D6MCF-7Ishikawa cellsSERMTNBCBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12575, p 12575 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tamoxifen CYP2D6 MCF-7 Ishikawa cells SERM TNBC Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	tamoxifen CYP2D6 MCF-7 Ishikawa cells SERM TNBC Biology (General) QH301-705.5 Chemistry QD1-999 Heba E. Elnakib Marian M. Ramsis Nouran O. Albably Merna A. Vector Jan J. Weigand Kai Schwedtmann Jannette Wober Oliver Zierau Günter Vollmer Ashraf H. Abadi Nermin S. Ahmed Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
description	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 <b>A</b>, <b>B,</b> and <b>C</b> 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 <b>12</b> (<i>E/Z</i>-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<sub>50</sub> = 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 <b>12</b> 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 <b>12</b> 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.
format	article
author	Heba E. Elnakib Marian M. Ramsis Nouran O. Albably Merna A. Vector Jan J. Weigand Kai Schwedtmann Jannette Wober Oliver Zierau Günter Vollmer Ashraf H. Abadi Nermin S. Ahmed
author_facet	Heba E. Elnakib Marian M. Ramsis Nouran O. Albably Merna A. Vector Jan J. Weigand Kai Schwedtmann Jannette Wober Oliver Zierau Günter Vollmer Ashraf H. Abadi Nermin S. Ahmed
author_sort	Heba E. Elnakib
title	Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
title_short	Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
title_full	Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
title_fullStr	Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
title_full_unstemmed	Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
title_sort	manipulating estrogenic/anti-estrogenic activity of triphenylethylenes towards development of novel anti-neoplastic serms
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/02806fab66f74a54bdf6c60bef1b845b
work_keys_str_mv	AT hebaeelnakib manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT marianmramsis manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT nouranoalbably manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT mernaavector manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT janjweigand manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT kaischwedtmann manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT jannettewober manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT oliverzierau manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT guntervollmer manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT ashrafhabadi manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms AT nerminsahmed manipulatingestrogenicantiestrogenicactivityoftriphenylethylenestowardsdevelopmentofnovelantineoplasticserms
_version_	1718411781119934464

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

Ejemplares similares