Bioorganic Chemistry, volume 104, pages 104324
Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency
Dezhenkova Lyubov G
3
,
Bykov Evgeny E
3
,
Solovieva Svetlana E.
3
,
Korlukov Alexander A
4
,
Sorokin Dmytro
2
,
Monzote Fidalgo Lianet
5
,
5
Department of Parasitology, Pedro Kouri Tropical Medicine Institute, Havana, Cuba
|
Publication type: Journal Article
Publication date: 2020-11-01
Journal:
Bioorganic Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.1
ISSN: 00452068, 10902120
Organic Chemistry
Drug Discovery
Biochemistry
Molecular Biology
Abstract
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.
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1 publication, 12.5%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Buravchenko G. I. et al. Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency // Bioorganic Chemistry. 2020. Vol. 104. p. 104324.
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Buravchenko G. I., Scherbakov A. M., Dezhenkova L. G., Bykov E. E., Solovieva S. E., Korlukov A. A., Sorokin D., Monzote Fidalgo L., Shchekotikhin A. Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency // Bioorganic Chemistry. 2020. Vol. 104. p. 104324.
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TY - JOUR
DO - 10.1016/j.bioorg.2020.104324
UR - https://doi.org/10.1016%2Fj.bioorg.2020.104324
TI - Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency
T2 - Bioorganic Chemistry
AU - Buravchenko, Galina I.
AU - Scherbakov, Alexander M.
AU - Dezhenkova, Lyubov G
AU - Bykov, Evgeny E
AU - Solovieva, Svetlana E.
AU - Korlukov, Alexander A
AU - Sorokin, Dmytro
AU - Monzote Fidalgo, Lianet
AU - Shchekotikhin, Andrey
PY - 2020
DA - 2020/11/01 00:00:00
PB - Elsevier
SP - 104324
VL - 104
SN - 0045-2068
SN - 1090-2120
ER -
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@article{2020_Buravchenko,
author = {Galina I. Buravchenko and Alexander M. Scherbakov and Lyubov G Dezhenkova and Evgeny E Bykov and Svetlana E. Solovieva and Alexander A Korlukov and Dmytro Sorokin and Lianet Monzote Fidalgo and Andrey Shchekotikhin},
title = {Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency},
journal = {Bioorganic Chemistry},
year = {2020},
volume = {104},
publisher = {Elsevier},
month = {nov},
url = {https://doi.org/10.1016%2Fj.bioorg.2020.104324},
pages = {104324},
doi = {10.1016/j.bioorg.2020.104324}
}