Design, synthesis and evaluation of Ospemifene analogs as anti-breast cancer agents

Kaur, Gurleen; Mahajan, Mohinder P.; Pandey, Manoj K.; Singh, Parvesh; Ramisetti, Srinivasa R.; Sharma, Arun

doi:10.1016/j.ejmech.2014.08.050

Cited by 21 publications

(16 citation statements)

References 13 publications

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“…Recently a novel ER agonist capable of inducing apoptotic death in various cancer cell was reported. Kaur and coworkers decribed Ospemifene analogues with stronger binding affinities with both ERα and ERβ compared to Ospemifene and Tamoxifen, exerting also cytotoxic effect on estrogen independent MDA-MB-231 cells [ 42 ]. On the other hand the novel entrogen receptor agonist inducing apoptotic death in various cancer cell types was described by Kim and coworkers [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

et al. 2016

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The cytotoxicity of 27 benzanilides and dithiobenzanilides built on a stilbene scaffold and possessing various functional groups in aromatic rings previously described for their spasmolytic properties was assayed on three human cancer cell lines (A549 –lung adenocarcinoma, MCF-7 estrogen dependent breast adenocarcinoma and MDA-MB-231 estrogen independent breast adenocarcinoma) and 2 non-tumorigenic cell lines (CCD39Lu–lung fibroblasts, MCF-12A - breast epithelial). Three compounds (6, 15 and 18) showed selective antiproliferative activity against estrogen dependent MCF-7 cancer cells and their estrogenic activity was further confirmed in MCF-7 transfected with an estrogen receptor reporter plasmid and in HEK239 cells over-expressing the estrogen receptor alpha (ERα). Compound 18 is especially interesting as a potential candidate for therapy since it is highly toxic and selective towards estrogen dependent MCF7 cell lines (IC50 = 5.07 μM versus more than 100 μM for MDA-MB-231) and almost innocuous for normal breast cells (IC50 = 91.46 μM for MCF-12A). Docking studies have shown that compound 18 interacts with the receptor in the same cavity as estradiol although the extra aromatic ring is involved in additional binding interactions with residue W383. The role of W383 and the extended binding mode were confirmed by site-directed mutagenesis.

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Section: Resultsmentioning

confidence: 99%

Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

et al. 2016

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“… 10 − 12 Furthermore, TAM has an adverse effect on endometrium causing endometrial cancer while raloxifene causes hot flashes, insomnia, dizziness, and melancholy. 13 …”

Section: Introductionmentioning

confidence: 99%

1H-1,2,3-Triazole Tethered Nitroimidazole–Isatin Conjugates: Synthesis, Docking, and Anti-Proliferative Evaluation against Breast Cancer

Kumar

Saha

et al. 2018

ACS Omega

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1H-1,2,3-Triazole tethered imidazole–isatin and imidazole–isatin–thiosemicarbazone conjugates were synthesized and evaluated against MCF-7 and MDA-MB-231 cell lines. Antiproliferative activities of the synthesized conjugates revealed an optimum combination of longer alkyl chain length as spacer and a halogen-substituent on the isatin ring as a pre-requisite for good activity. The compound 6g with an optimum combination of chloro-substituent at C-5 position of isatin ring and a butyl chain length proved to be most active and noncytotoxic with IC50s of 54.25 and 26.12 μM against MCF-7 and MDA-MB-231 cell lines, respectively.

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“…Although the mechanism underlying the anticancer effect of NJK14013 is not clear, it does not appear to be dependent on its ER-modulating activity since NJK14013 showed similar effects on ER-negative cancer cells. Interestingly, a recent study identified ospemifene derivatives that were cytotoxic to both MCF7 and MDA-MB-231, despite the fact that ospemifene itself is selective for ER-positive MCF7; moreover, these compounds were not toxic to normal mouse embryonic fibroblasts (25). Thus, it is conceivable that some SERMs may be able to acquire ER-independent, cancer cell-specific cytotoxicity while retaining ER-modulating activity.…”

Section: Discussionmentioning

confidence: 99%

NJK14013, a novel synthetic estrogen receptor-α agonist, exhibits estrogen receptor-independent, tumor cell-specific cytotoxicity

Kim

et al. 2015

International Journal of Oncology

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Abstract. Estrogens act through interactions with estrogen receptors (ERs) to play diverse roles in various pathophysiological conditions. A number of synthetic selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been developed and used to treat ER-related diseases, including breast cancer and osteoporosis. Here, we identified a novel compound, bis(4-hydroxyphenyl) methanone-O-isopentyl oxime, designated NJK14013, as an ER agonist. NJK14013 activated ER-dependent transcription in a concentration-dependent manner, while suppressing androgen receptor-dependent transcriptional activity. It induced the activation-related phosphorylation of ER and enhanced the transcription of growth regulation by estrogen in breast cancer 1 (GREB1), further supporting its ER-stimulating activity. NJK14013 exerted anti-proliferative effects on various cancer cell lines, including an ER-negative breast cancer cell line, suggesting that it is capable of suppressing the growth of cancer cells independent of its ER-modulating activity. In addition, NJK14013 treatment resulted in significant apoptotic death of MCF7 and Ishikawa cancer cells, but did not induce apoptosis in non-cancer human umbilical vein endothelial cells. Collectively, our findings demonstrate that NJK14013 is a novel SERM that can activate ER-mediated transcription in MCF7 cells and suppress the proliferation of various cancer cells, including breast cancer cells and endometrial cancer cells. These results suggest that NJK14013 has potential as a novel SERM for anticancer or hormone-replacement therapy with reduced risk of carcinogenesis.

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Design, synthesis and evaluation of Ospemifene analogs as anti-breast cancer agents

Cited by 21 publications

References 13 publications

Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

1H-1,2,3-Triazole Tethered Nitroimidazole–Isatin Conjugates: Synthesis, Docking, and Anti-Proliferative Evaluation against Breast Cancer

NJK14013, a novel synthetic estrogen receptor-α agonist, exhibits estrogen receptor-independent, tumor cell-specific cytotoxicity

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