Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells

Abstract

Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulphonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel. However, the napthyl analog diminished gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules upregulate ERβ activity while down regulating that of ERα.

Design, synthesis, anticancer activity, molecular docking and ADME studies of novel methylsulfonyl indole-benzimidazoles in comparison with ethylsulfonyl counterparts

“…3,19 Methyl or naphthyl attached benzimidazole structures also demonstrate SERMlike actions on breast cancer cell lines. 3,[19][20][21] In line with the above-mentioned findings, we have previously identified several ethylsulfonyl indole-benzimidazole derivatives with antiestrogenic properties. 22 Interestingly, antiproliferative effects were distinct based on ER status where ERa-positive cell lines MCF-7 and HEPG2 resulted in overlapping cell viability profiles across various compound concentrations in comparison with ERa-negative cell line MDA-MB-231.…”

“…In addition to the widely used first generation SERM known as tamoxifen, 11,12 there are other second and third generation SERMs developed to reduce side effects associated with tamoxifen. 11,13 For instance, the affinity of third generation bazedoxifene is more selective towards the ERa rather than ERb, hence its inhibitory effect progresses through ERa downregulation and cell cycle arrest. 11 In addition, bazedoxifene with palbociclib combination is a promising therapeutic option in clinics, and tested against metastatic BC at stage IV.…”

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles

“…A quick look at the literature shows several works on derivatives of BZM, BTA, and BOX, especially those substituted at the 2 position, which have shown important biological activity against different types of neoplasms, including breast cancer [ 36 , 37 , 38 , 39 , 40 ]. It has been pointed out that the mechanisms of action of these benzo [ d ] [1,3] azole are different, highlighting in an important way the signaling pathways modulated by ERs [ 41 , 42 , 43 , 44 ]. Thus, following our continuous interest in the synthesis of benzofused heterocyclic derivatives and the study of their potential biological activities, in this opportunity, we report here the synthesis and characterization of a series of benzo [ d ] [1,3] azoles substituted at position 2 with benzyl and allyl-sulfanyl groups ( BTA-1 , BZM-2 , BOX-3 , BTA-4 , BZM-5 and BOX-6 ) and their preliminary in vitro cytotoxic assays against different human cancer cell lines.…”

Rapid and Efficient Synthesis of a New Series of 2-Aryl-5-Fluoro-6-(4-Phenylpiperazin-1-Yl)-1H-Benzimidazoles Using Microwave Heating

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Benzimidazoles have generated a great deal of interest because of their important roles in organic synthesis and the pharmaceutical industry. [1][2][3][4][5][6][7] The benzimidazole system can be found in some medicinal compounds such as omeprazole, thiabendazole and albendazole. [8][9][10][11][12] Recently, it was reported that some benzimidazoles derivatives containing fluorine atom and 1-piperazinyl moiety have a valuable biological activity.

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“…The iminoester hydrochlorides were synthesised according to the Pinner method. 24 Then, these compounds were reacted with compound 2 to synthesise the corresponding benzimidazole derivatives (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).The synthesis of 4-fluoro-5-(4-phenylpiperazin-1-yl) benzene-1,2-diamine (2) was performed under microwave irradiation in ethanol by using Pd/C (10%) catalyst and hydrazine monohydrate. Using this method, the compound was easily synthesised in good yield without the need for further purification before the next step.…”