Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic.
Eur J Med Chem
; 259: 115647, 2023 Nov 05.
Article
em En
| MEDLINE
| ID: mdl-37478557
ABSTRACT
The discovery of selective agonists of cannabinoid receptor 2 (CB2) is strongly pursued to successfully tuning endocannabinoid signaling for therapeutic purposes. However, the design of selective CB2 agonists is still challenging because of the high homology with the cannabinoid receptor 1 (CB1) and for the yet unclear molecular basis of the agonist/antagonist switch. Here, the 1,3-benzoxazine scaffold is presented as a versatile chemotype for the design of CB2 agonists from which 25 derivatives were synthesized. Among these, compound 7b5 (CB2 EC50 = 110 nM, CB1 EC50 > 10 µM) demonstrated to impair proliferation of triple negative breast cancer BT549 cells and to attenuate the release of pro-inflammatory cytokines in a CB2-dependent manner. Furthermore, 7b5 abrogated the activation of extracellular signal-regulated kinase (ERK) 1/2, a key pro-inflammatory and oncogenic enzyme. Finally, molecular dynamics studies suggested a new rationale for the in vitro measured selectivity and for the observed agonist behavior.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzoxazinas
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article