Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency
| Autor: | Danila V. Sorokin, Andrey E. Shchekotikhin, Lianet Monzote Fidalgo, Alexander M. Scherbakov, Galina I. Buravchenko, Alexander A. Korlukov, Lyubov G. Dezhenkova, Svetlana E. Solovieva, Evgeny E. Bykov |
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| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Poly ADP ribose polymerase Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Quinoxaline Cell Line Tumor Quinoxalines Diamine Nitriles Drug Discovery Humans Cytotoxicity Molecular Biology Cell Proliferation Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia 0104 chemical sciences 010404 medicinal & biomolecular chemistry Receptors Estrogen chemistry Cell culture Drug Screening Assays Antitumor Tirapazamine K562 cells |
| Zdroj: | Bioorganic Chemistry. 104:104324 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.104324 |
| Popis: | In this article, we describe the synthesis of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides bearing cyclic diamine residues at positions 6 or 7; the synthesis is based on the nucleophilic substitution of halogens. All synthesized 6(7)-aminoquinoxaline-2-carbonitrile 1,4-dioxides 3-6 demonstrated higher cytotoxicity and hypoxia selectivity compared to the reference agent tirapazamine against breast adenocarcinoma cell lines (MCF7, MDA-MB-231). The structure and position of the diamine residue considerably affects the antiproliferative properties of the quinoxaline-2-carbonitrile 1,4-dioxides. The introduction of a halogen atom at position 7 in the quinoxaline ring of 4a considerably increases the cytotoxicity of compounds 5a and 6a under both normoxic and hypoxic conditions. However, the most hypoxia-selective derivatives were non-halogenated 7-aminosubstituted 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides 3a-j. Of the 32 novel synthesized derivatives, approximately 20 of the 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides demonstrated high antiproliferative potency against wild type leukemia cells K562 and drug-resistant subline K562/4 with the expression of p-glycoprotein (p-gp) compared to the reference agent doxorubicin, which exhibited one order of magnitude lower activity towards K562/4 cells than towards K562 cells. Lead compounds 5a and 3f inhibited HIF-1α expression and activity and induced apoptosis in hypoxic tumor cells, which was confirmed by poly(ADP-ribose)polymerase (PARP) cleavage. Moreover, 5a and 3f showed strong antiestrogenic potencies in MCF7 breast cancer cells. Thus, the described series of quinoxaline 1,4-dioxides has high anticancer potential and good aqueous solubility. Therefore, these compounds are promising for further drug development of hypoxia-targeted anticancer agents. |
| Databáze: | OpenAIRE |
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