Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy.
Eur J Med Chem
; 240: 114560, 2022 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-35777102
ABSTRACT
Novel tolfenamic acid derivatives based on the structure of I-1 were designed and synthesized to improve its poor target inhibition and solubility. Among them, W10 was identified as a potent dual-target inhibitor of Topo I (IC50 = 0.90 ± 0.17 µM) and COX-2 (IC50 = 2.31 ± 0.07 µM) with improved water solubility (32.33 µg/mL). Moreover, W10 also exhibited fairly potent anti-proliferative and pro-apoptosis activity via the mitochondrial pathway, as well as suppressed aberrant NF-κB/IκB activation in colon cancer cells in vitro. Additionally, W10 possessed favorable pharmacokinetic properties and excellent antitumor effects in vivo. In general, our study has demonstrated the potency of a novel Topo I/COX-2 dual inhibitor, which can potentially be developed into a chemotherapeutic candidate for colon cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Colon_e_reto
Base de dados:
MEDLINE
Assunto principal:
Neoplasias do Colo
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China