Abstract
A series of estrone derivatives 3⁻8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future.
Keywords:
anticancer evaluation; design; estrogen derivatives; molecular modeling studies.
MeSH terms
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Animals
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Antineoplastic Agents, Hormonal / chemical synthesis
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Antineoplastic Agents, Hormonal / chemistry*
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Antineoplastic Agents, Hormonal / pharmacology*
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Binding Sites
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Estrogens / analogs & derivatives
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Estrogens / chemical synthesis
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Estrogens / chemistry*
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Estrogens / pharmacology*
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Female
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Humans
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Inhibitory Concentration 50
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Mice
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Models, Molecular*
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Molecular Structure
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Protein Binding
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Quantitative Structure-Activity Relationship
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitination / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Hormonal
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Estrogens
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Protein Kinase Inhibitors
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Tumor Suppressor Protein p53