A2A receptor antagonist 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol, a promising adenosine derivative for glioblastoma treatment

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-02-10 DOI:10.1016/j.ejps.2025.107039
Akshaya Murugesan , Aleksei Smirnov , Anxo Vila Alonso , Michela Buccioni , Chang Cui , Diego Dal Ben , Beatrice Francucci , Catia Lambertucci , Gabriella Marucci , Rosaria Volpini , Saravanan Konda Mani , Sandhanasamy Devanesan , Mohamad S. AlSalhi , Olli Yli-Harja , Andrea Spinaci , Meenakshisundaram Kandhavelu
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Abstract

Adenosine, a pervasive signaling molecule mediated by its interaction with G-protein-coupled receptor subtypes, especially the A2A adenosine receptor (A2AAR), plays a crucial role in cancer treatment. Recently, A2AAR targeting adenosine analogs have been proposed as a potential therapeutic target for cancer treatment. However, the molecules targeting A2AAR and their mode of action in inhibiting glioblastoma cell progression remain unknown. We synthesized six adenosine derivatives substituted at the 9-, 2- and/or N6- and/or 8- positions, and their anti-proliferative efficacy against the GBM cell lines LN229 and SNB19 was assessed. Molecular dynamic simulation integrated with experimental analyses, including cell cycle arrest, apoptosis assay, ligand binding assay, absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, PAMPA assay, and 3D spheroid analysis, were performed to identify the interaction efficacy of the potential derivative with A2AAR and its ability to prevent GBM cell progression. The most potent A2AAR derivative (ANR), 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol (ANR 672) inhibits 5′-N-Ethylcarboxamidoadenosine (NECA)-induced cAMP validating the antagonistic property with higher cytotoxicity effect against GBM cells. ANR 672 showed higher affinity toward A2AAR (Ki = 1.02 ± 0.06 nM) and exhibited significant IC50 concentrations of ∼ 60–80 µM, than FDA approved drug istredefylline. The A2AAR-ANR 672 interaction profile showed well-defined hydrogen bonds and hydrophobic contacts, indicating a typical binding mechanism inside the receptor pocket and a higher degree of conformational flexibility than the A2AAR-Istradefylline complex. The antagonist effect of ANR 672 blocked the A2AAR signaling pathway, leading to necrosis-mediated cell death and cell cycle arrest at the S-phase in both the GBM cells. ANR 672 treated 3D tumour spheroids analysis with real-time spheroid volume and cell proliferation analysis revealed the potential ability of ANR 672 against GBM cell growth. Drug-likeness assessments also showed favorable pharmacokinetic profiles for ANR 672. Further validation of blood-brain barrier crossing potential revealed that ANR 672 possesses moderate permeability. Our findings shed light on how ANR 672 exerts its GBM-suppressive effect through the interaction of A2AAR. These preclinical results suggest that A2AAR blockade could be a unique strategy for treating GBM.

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期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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