Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents.
Eur J Med Chem
; 169: 168-184, 2019 May 01.
Article
em En
| MEDLINE
| ID: mdl-30877972
ABSTRACT
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50â¯=â¯6.43-10.97⯵M for F10, HeLa, A549 and MCF-7â¯cells), lower toxicity to non-cancer cells than celecoxib (A33 IC50â¯=â¯194.01⯵M vs.celecoxib IC50â¯=â¯97.87⯵M for 293T cells), and excellent inhibitory activities on COX-2 (IC50â¯=â¯0.17⯵M) and 5-LOX (IC50â¯=â¯0.68⯵M). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10â¯cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Azóis
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Araquidonato 5-Lipoxigenase
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Morfolinas
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Inibidores de Lipoxigenase
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Ciclo-Oxigenase 2
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Inibidores de Ciclo-Oxigenase 2
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article