1. Identification of the hydantoin alkaloids parazoanthines as novel CXCR4 antagonists by computational and in vitro functional characterization
- Author
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Genoveffa Nuzzo, Maria Letizia Ciavatta, Stefano Thellung, Efstathia Ioannou, Emiliano Manzo, Tullio Florio, Agnese Solari, Monica Gatti, Pietro Amodeo, Rosa Maria Vitale, Vassilios Roussis, and Francesco Tinto
- Subjects
Receptors, CXCR4 ,In silico ,parazoanthines natural products ,Hydantoin ,Structure-activity relationships ,Parazoanthus axinellae ,Natural compounds ,01 natural sciences ,Biochemistry ,Chemokine receptor ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alkaloids ,Hydantoin alkaloids ,Drug Discovery ,Animals ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Hydantoin alkaloids, parazoanthines natural products, CXCR4 antagonists, molecular docking, pharmacophoric model ,Cloning, Molecular ,Receptor ,Molecular Biology ,CXCR4 ,antagonists ,CXCR4 antagonist ,biology ,010405 organic chemistry ,Chemistry ,Hydantoins ,Organic Chemistry ,molecular docking ,CXCL12 ,organic synthesis ,biology.organism_classification ,Anthozoa ,Small molecule ,In vitro ,0104 chemical sciences ,Rats ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,CXCR4 antagonists ,pharmacophoric model ,Signal Transduction - Abstract
CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure–activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.
- Published
- 2020
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