Abstract
The overexpression of the A3 adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new A3AR ligands, a series of novel 2,N6-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the N6-position were found to exert higher A3AR affinity and selectivity than the corresponding N6-(2,2-diphenylethyl) analogues. 2-Chloro-N6-phenylethylAdo (15) was found to be a potent full A3AR agonist with a Ki of 0.024 nM and an EC50 of 14 nM, in a cAMP accumulation assay. Unlike 15, the other ligands behaved as A3AR antagonists, which concentration-dependently reduced cell growth and exerted cytostatic activity on the prostate cancer cell line PC3, showing comparable and even more pronounced effects with respect to the ones elicited by the reference full agonist Cl-IB-MECA. In particular, the N6-(2,2-diphenylethyl)-2-phenylethynylAdo (12: GI50 = 14 µM, TGI = 29 µM, and LC50 = 59 µM) showed the highest activity proving to be a potential antitumor agent. The cytostatic effect of both A3AR agonist (Cl-IB-MECA) and antagonists (12 and other newly synthesized compounds) confirm previous observations according to which, in addition to the involvement of A3ARs, other cellular mechanisms are responsible for the anticancer effects of these ligands.
Highlights
Ubiquitous nucleosides and nucleotides are involved in several biological functions and they play a crucial role in some mechanisms, such as cell growth, migration, differentiation, bacterial-induced inflammation and growth factor secretion [1,2,3,4]
We report the synthesis of the newly nucleosides 10–13, 15, and 16, together with that of the previously reported compounds 4 and 5, which was carried out using a divergent approach starting from commercial guanosine (Schemes 1 and 2)
Results showed that the reference compound Cl-IB-MECA and the 2-chloro-N6phenethylAdo (15) were able to completely counteract the stimulation of adenylyl cyclase induced by 10 μM forskolin, so behaving as A3AR full agonists
Summary
Ubiquitous nucleosides and nucleotides are involved in several biological functions and they play a crucial role in some mechanisms, such as cell growth, migration, differentiation, bacterial-induced inflammation and growth factor secretion [1,2,3,4]. The nucleoside adenosine (Ado, 1, Figure 1) performs its function by interacting with the four A1, A2A, A2B and A3 adenosine receptors (ARs) belonging to the superfamily of G protein-coupled receptors (GPCRs). The activation of A1AR and A3AR mainly produces a decrease of the intracellular cyclic adenosine monophosphate (cAMP) concentration, while stimulation of the A2AAR and A2BAR leads to an opposite effect.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
