A₃ Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• The A3 adenosine receptor (AR) is overexpressed in various cancer cells, making it a significant target for cancer diagnosis and treatment.
• Developing selective ligands for the A3AR is crucial for advancing targeted cancer therapies.

Purpose of the Study:

• To synthesize and evaluate novel 2,N6-disubstituted adenosine derivatives as potential A3AR ligands.
• To investigate the binding affinity, selectivity, and functional activity of these compounds at A3ARs.
• To assess the antitumor potential of these novel ligands against cancer cell lines.

Main Methods:

• Synthesis of a series of novel 2,N6-disubstituted adenosine derivatives.
• Radioligand binding assays to determine A3AR affinity and selectivity.
• Functional assays (e.g., cAMP accumulation) to assess agonist/antagonist activity.
• Cell-based assays to evaluate cytostatic and cytotoxic effects on prostate cancer cell line PC3.

Main Results:

• Certain derivatives with a 2-phenethylamino group exhibited higher A3AR affinity and selectivity.
• Compound 15, 2-chloro-N6-phenylethylAdo, demonstrated potent full A3AR agonism (Ki = 0.024 nM).
• Other synthesized ligands acted as A3AR antagonists, showing concentration-dependent inhibition of PC3 cell growth, with compound 12 (N6-(2,2-diphenylethyl)-2-phenylethynylAdo) exhibiting significant antitumor activity (GI50 = 14 µM, TGI = 29 µM, LC50 = 59 µM).

Conclusions:

• Novel 2,N6-disubstituted adenosines represent a promising class of compounds for A3AR-targeted cancer therapy.
• Both A3AR agonists and antagonists derived from this series display significant anticancer effects.
• The observed cytostatic effects suggest that A3ARs, along with other cellular mechanisms, play a role in the anticancer activity of these ligands.