%0 Journal Article
%A Gambacorta, Nicola
%A Gasperi, Valeria
%A Guzzo, Tatiana
%A Saverio Di Levada, Francesco
%A Ciriaco, Fulvio
%A Sánchez García, María Cristina
%A Tullio, Valentina
%A Rozzi, Diego
%A Marinelli, Luciana
%A Topai, Alessandra
%A Nicolotti, Orazio
%A Maccarrone, Mauro
%T Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic
%D 2023
%@ 0223-5234
%U https://hdl.handle.net/20.500.14352/102415
%X 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.
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