Design, synthesis, and pharmacological evaluation of sinomenine derivatives on rings A and C: Novel compounds screening for aplastic anemia targeting on cytotoxic T lymphocyte.
Eur J Med Chem
; 225: 113791, 2021 Dec 05.
Article
en En
| MEDLINE
| ID: mdl-34450495
ABSTRACT
Cytotoxic T lymphocyte (CTL), a key effector cell in aplastic anemia (AA) immune injury, is shown to be a potential target for AA drug therapy. However, there is no candidate for this target till now. Oriented by the inhibition activity of CTL and macrophage derived nitric oxide (NO), a series of novel sinomenine derivatives on rings A and C are designed, synthesized and screened. Among them, compound 3a demonstrates the best inhibitory activity on CTL with an IC50 value of 2.3 µM, and a 97.1% inhibiton rate on macrophage NO production without significant cytotoxicity. Further, compound 3a exhibits substantial therapeutic efficacy on immune-mediated BM failure in AA model mice by improving the symptoms of anemia and the function of BM hematopoiesis, and shows more advantages in life quality improving than cyclosporine A (CsA). Its efficacy on AA at least partly comes from targeting on activated cluster of differentiation (CD)8+ T cell. Additionally, 3a also shows much less toxicity (LD50 > 10.0 g/kg) than sinomenine (LD50 = 1.1 g/kg) in preliminary acute toxicity assessment in mice, and has a low risk to inhibit hERG to cause cardiotoxicity. These results indicate that compound 3a merits further investigation for AA treatment by targeting on CTL.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos T Citotóxicos
/
Diseño de Fármacos
/
Antirreumáticos
/
Anemia Aplásica
/
Morfinanos
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Año:
2021
Tipo del documento:
Article