Discovery of novel trimethoxyphenylbenzo[d]oxazoles as dual tubulin/PDE4 inhibitors capable of inducing apoptosis at G2/M phase arrest in glioma and lung cancer cells.
Eur J Med Chem
; 224: 113700, 2021 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-34311158
ABSTRACT
To discover PDE4/tubulin dual inhibitors with novel skeleton structures, 7-trimethoxyphenylbenzo[d]oxazoles 4a-u and 4-trimethoxyphenylbenzo[d]oxazoles 5a-h were designed and synthesized by migrating the trimethoxyphenyl group of TH03 to the benzo[d]oxazole moiety. Among these compounds, approximately half of them displayed good antiproliferative activities against glioma (U251) and lung cancer (A549 and H460) cell lines. The structure-activity relationships of trimethoxyphenylbenzo[d]oxazoles led to the identification of 4r bearing indol-5-yl side-chain as a novel dual PDE4/tubulin inhibitor, which exhibited satisfactory antiproliferative activities against glioma (IC50 = 300 ± 50 nM) and lung cancer (average IC50 = 39.5 nM) cells. Further investigations revealed that 4r induced apoptosis at G2/M phase arrest and disrupted the microtubule network. The preliminary mechanism of action showed that 4r down-regulated the expression of cyclin B1 and its upstream regulator gene cdc25C in A549.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Oxazóis
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Tubulina (Proteína)
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Apoptose
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Moduladores de Tubulina
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 4
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Descoberta de Drogas
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Inibidores da Fosfodiesterase 4
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Glioma
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2021
Tipo de documento:
Article