A3 Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity

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.

2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives

“…For example, A 1 ligands are useful for glaucoma, heart failure, angina, seizures, ischemia, depression, obesity, asthma, renal protection, edema associated with congestive heart failure, atrial arrhythmias, type II diabetes, neuropathic pain, neuroprotection, atrial fibrillation, tachycardia, cardioprotection, and sleep regulation [ 1 , 8 , 9 , 10 , 11 , 12 ]. In addition, A 3 ligands are useful for liver regeneration, hepatitis, psoriasis, rheumatoid arthritis, inflammation, dry eye syndrome, fibrotic diseases, neurodegeneration, ischaemia, asthma, chronic obstructive pulmonary disease, glaucoma, and cancer [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], with A 3 antagonist PBF-677 (Palobiofarma SL), that has reached clinical trials for glaucoma, ulcerative colitis, and eosinophilic esophagitis [ 21 , 22 ]. Finally, dual A 1 /A 3 ligands can be useful as potential therapeutics for treating glaucoma, kidney failure, pulmonary diseases, and Alzheimer’s disease [ 23 , 24 ].…”

Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors

“…Considering the large distribution of adenosine in the organism, it is quite evident that adenosine receptors could be considered an important target for the treatment of several pathologies. In fact, in the last decades, different classes of potent and selective agonists and antagonists have been reported with the aim of characterizing and better understanding the pathophysiological role of adenosine receptor subtypes and their possible involvement in several disorders [5][6][7][8][9][10][11]. In particular, A 1 antagonists are investigated for their effect on both cardiovascular and metabolic diseases [7]; A 2A and A 2B antagonists are attracting increasing attention as cancer immunotherapy agents, while A 2A is also under study for the treatment of neurodegenerative disorders (i.e., istradefylline is already approved as adjunctive therapy to levodopa in Parkinson's disease) [9,10]; and, finally, A 3 antagonists proved effective in preclinical animal models of brain ischemia and oxygen-glucose deprivation in hippocampal slices [6][7][8][9][10][11].…”