RT Journal Article
T1 Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic
A1 Gambacorta, Nicola
A1 Gasperi, Valeria
A1 Guzzo, Tatiana
A1 Saverio Di Levada, Francesco
A1 Ciriaco, Fulvio
A1 Sánchez García, María Cristina
A1 Tullio, Valentina
A1 Rozzi, Diego
A1 Marinelli, Luciana
A1 Topai, Alessandra
A1 Nicolotti, Orazio
A1 Maccarrone, Mauro
AB 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.
PB Elsevier
SN 0223-5234
YR 2023
FD 2023-07-14
LK https://hdl.handle.net/20.500.14352/102415
UL https://hdl.handle.net/20.500.14352/102415
LA eng
NO Italian Ministry of University and Research (MUR)
NO University of L'Aquila
NO Università degli Studi di Bari (Bari, Italy)
NO Horizon Europe Seeds
NO Regione Lazio – DTB – Fondi CIPE
DS Docta Complutense
RD 10 abr 2025