51. Design, synthesis and anticancer/antiestrogenic activities of novel indole-benzimidazoles.
- Author
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Karadayi FZ, Yaman M, Kisla MM, Keskus AG, Konu O, and Ates-Alagoz Z
- Subjects
- Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Benzimidazoles metabolism, Benzimidazoles pharmacology, Binding Sites, Cell Line, Tumor, Cell Proliferation drug effects, Cluster Analysis, Drug Screening Assays, Antitumor, Estrogen Antagonists metabolism, Estrogen Antagonists pharmacology, Estrogen Receptor alpha chemistry, Estrogen Receptor alpha metabolism, Humans, Indoles chemistry, Molecular Docking Simulation, Principal Component Analysis, Signal Transduction, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Benzimidazoles chemistry, Drug Design, Estrogen Antagonists chemical synthesis
- Abstract
Indole-benzimidazoles have recently gained attention due to their antiproliferative and antiestrogenic effects. However, their structural similarities and molecular mechanisms shared with selective estrogen receptor modulators (SERMs) have not yet been investigated. In this study, we synthesized novel ethylsulfonyl indole-benzimidazole derivatives by substituting the first (R
1 ) and fifth (R2 ) positions of benzimidazole and indole groups, respectively. Subsequently, we performed1 H NMR,13 C NMR, and Mass spectral and in silico docking analyses, and anticancer activity screening studies of these novel indole-benzimidazoles. The antiproliferative effects of indole-benzimidazoles were found to be more similar between the estrogen (E2) responsive cell lines MCF-7 and HEPG2 in comparison to the Estrogen Receptor negative (ER-) cell line MDA-MB-231. R1 :p-fluorobenzyl group members were selected as lead compounds for their potent anticancer effects and moderate structural affinity to ER. Microarray expression profiling and gene enrichment analyses (GSEA) of the selected compounds (R1 :p-fluorobenzyl: 48, 49, 50, 51; R1 :3,4-difluorobenzyl: 53) helped determine the similarly modulated cellular signaling pathways among derivatives. Moreover, we identified known compounds that have significantly similar gene signatures to that of 51 via queries performed in LINCS database; and further transcriptomics comparisons were made using public GEO datasets (GSE35428, GSE7765, GSE62673). Our results strongly demonstrate that these novel indole-benzimidazoles can modulate ER target gene expression as well as dioxin-mediated aryl hydrocarbon receptor and amino acid deprivation-mediated integrated stress response signaling in a dose-dependent manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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