Design and synthesis of dual cathepsin L and S inhibitors and antimetastatic activity evaluation in pancreatic cancer cells.
Bioorg Med Chem Lett
; 80: 129087, 2023 01 15.
Article
em En
| MEDLINE
| ID: mdl-36427655
ABSTRACT
Currently, the migration and invasion of cancer cells remain the main factors of poor prognosis in the majority of cancer patients. Developing an effective antimetastatic agent is crucial for cancer therapy. Our recent research revealed that Cat L and S are expressed concurrently in metastatic pancreatic cancer cells. Asperphenamate analog ASPER-29, which exhibits dual Cat L and S inhibitory potency, showed a definite antimetastatic effect on pancreatic cancer BxPC-3 and PANC-1 cells. To further improve the antimetastatic ability of asperphenamate-type molecules, 24 derivatives were designed and synthesized by a scaffold-hopping strategy. The cathepsin inhibitory activity assay results showed that most of the derivatives exhibited dual inhibitory effects on Cat L and S. Among all derivatives, Compound B1a showed the strongest inhibitory activity, with IC50 values of 4.10 ± 0.14 µM and 1.79 ± 0.11 µM, which were 1.5-fold and 2.8-fold more potent than those of positive drugs against Cat L and S, respectively. Further wound-healing and transwell chamber assays demonstrated that B1a presented significant antimetastatic ability in vitro.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article