ArticleJournal of medicinal chemistry2005
"Reversine" and its 2-substituted adenine derivatives as potent and selective A3 adenosine receptor antagonists.
Article in Journal of medicinal chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 64 citations in OpenAlex.
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- Aza-Reversine Promotes Reprogramming of Lung (MRC-5) and Differentiation of Mesenchymal Cells into Osteoblasts.Materials (Basel, Switzerland) · 2021Article
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
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- Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells.Molecules (Basel, Switzerland) · 2018Article
- AMedicinal research reviews · 2018Review
- Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study.Molecules (Basel, Switzerland) · 2018Article
- 3D-e-Chem: Structural Cheminformatics Workflows for Computer-Aided Drug Discovery.ChemMedChem · 2018Article
- Reversine, a substituted purine, exerts an inhibitive effect on human renal carcinoma cells via induction of cell apoptosis and polyploidy.OncoTargets and therapy · 2018Article
- Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells.PloS one · 2016Article
- Synthesis and anti-renal fibrosis activity of conformationally locked truncated 2-hexynyl-N(6)-substituted-(N)-methanocarba-nucleosides as A3 adenosine receptor antagonists and partial agonists.Journal of medicinal chemistry · 2014Article
- Targeting focal adhesion turnover in invasive breast cancer cells by the purine derivative reversine.British journal of cancer · 2013Article
- H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4.American journal of respiratory cell and molecular biology · 2013Article
- Error-prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Reversine suppresses oral squamous cell carcinoma via cell cycle arrest and concomitantly apoptosis and autophagy.Journal of biomedical science · 2012Article
- Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A₂A and A₃ adenosine receptor ligands.Journal of medicinal chemistry · 2012Article
- Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold.Bioorganic & medicinal chemistry letters · 2011Article
- Discovery of New Human A(2A) Adenosine Receptor Agonists: Design, Synthesis, and Binding Mode of Truncated 2-Hexynyl-4'-thioadenosine.ACS medicinal chemistry letters · 2010Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K(i) value of 0.66 microM. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N(6)-cyclohexyladenine (12), 2-(phenylamino)-N(6)-cycloheptyladenine (19), and 2-phenylamino-N(6)-endo-norbornyladenine (21) as potent A(3) AR ligands with K(i) values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (>200-fold) was 2-(phenyloxy)-N(6)-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy > or = amino > thio. Selected derivatives, including reversine (K(B) value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N(6) position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation.
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