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  3. Exploring Trisubstituted adenine derivatives as adenosine A1 receptor ligands with antagonist activity: Synthesis, biological evaluation and molecular modelling

Exploring Trisubstituted adenine derivatives as adenosine A1 receptor ligands with antagonist activity: Synthesis, biological evaluation and molecular modelling

  • Bioorg Chem. 2025 Jun 1:159:108395. doi: 10.1016/j.bioorg.2025.108395.
Laura B Córdoba-Gómez 1,  Álvaro Lorente-Macías 2,  María Isabel Loza 3,  José Brea 3,  Antón Leandro Martínez 3,  Jonathon Mok 2,  Ben King 2,  Francisco Franco-Montalban 1,  Antonio González García 1,  Juan José Guardia-Monteagudo 4,  Maria J Matos 5,  Asier Unciti-Broceta 2,  Juan José Díaz-Mochón 6,  Maria Jose Pineda de Las Infantas 7
Affiliations

Affiliations

  • 1 Departamento Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain.
  • 2 Edinburgh Cancer Research, Institute of Genetics and Cancer, The University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK; Cancer Research UK Scotland Centre, UK.
  • 3 Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, CIMUS Research Center, Santiago de Compostela, Spain.
  • 4 DESTINA Genomica SL, Avenida de la Innovación 1, 18016 Granada, Spain.
  • 5 Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: mariajoao.correiapinto@usc.es.
  • 6 Departamento Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain; GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government. PTS Granada - Avenida de la Ilustración, 114, 18016, Granada, Spain; Unit of Excellence in Chemistry Applied to Biomedicine and the Environment of the University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain. Electronic address: juandiaz@go.ugr.es.
  • 7 Departamento Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain. Electronic address: mjpineda@ugr.es.
PMID: 40154234 DOI: 10.1016/j.bioorg.2025.108395
Abstract

The therapeutic potential of Adenosine Receptor (AR) ligands is becoming increasingly important as our understanding of the physio-pathological functions of ARs advances. This study presents the synthesis and biological screening of six novel trisubstituted adenine analogues, expanding a previously reported series. The AR binding affinity and antiproliferative activity were evaluated for both the new and previously reported compounds, leading to the discovery of derivatives that displaying selective binding affinity towards hA1AR. Compounds were synthesized using a cyclization approach by combining 4,6-bisalkylamino-5-aminopyrimidines with three different trialkyl/arylorthoesters, thereby generating adenines featuring three different substituents at the 8 position: H, methyl or phenyl. Most promising derivatives presented a phenyl ring at such position and displayed selective antagonistic activity against hA1AR. N6,9-diisopropyl-8-phenyl-9H-purin-6-amine (14c) was identified as the most potent compound with a Ki of 2 nM, motivating the synthesis of new derivatives including N6,9-dicyclopentyl-8-phenyl-9H-purin-6-amine (19c). Docking modelling predicted key interactions between the lead compounds and hA1AR. Determination of their anti-proliferative activity on six Cancer cell lines found 19c to be the most potent derivative with low micromolar EC50 values. Our findings support further exploration around the adenine scaffold for Cancer research and AR drug development.

Keywords

Adenine scaffold; Antiproliferation; Docking simulation; Orthosteric binding site; Pharmacokinetic properties; Selectivity index; cancer cell lines.

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