@article{3020614,
    title = "Identification of the hydantoin alkaloids parazoanthines as novel CXCR4 antagonists by computational and in vitro functional characterization",
    author = "Vitale, R.M. and Thellung, S. and Tinto, F. and Solari, A. and Gatti, M. and Nuzzo, G. and Ioannou, E. and Roussis, V. and Ciavatta, M.L. and Manzo, E. and Florio, T. and Amodeo, P.",
    journal = "Bioorganic Chemistry",
    year = "2020",
    volume = "105",
    publisher = "Academic Press Inc.",
    issn = "0045-2068, 1090-2120",
    doi = "10.1016/j.bioorg.2020.104337",
    keywords = "alkaloid;  chemokine receptor CXCR4;  chemokine receptor CXCR4 antagonist;  functional group;  hydantoin;  messenger RNA;  mitogen activated protein kinase 1;  mitogen activated protein kinase 3;  parazoanthine a;  parazoanthine b;  parazoanthine c;  unclassified drug;  alkaloid;  chemokine receptor CXCR4;  hydantoin derivative, Anemone;  animal cell;  Article;  computer model;  controlled study;  drug efficacy;  drug identification;  drug potency;  drug synthesis;  gene overexpression;  IC50;  in vitro study;  molecular docking;  nonhuman;  pharmacophore;  priority journal;  structure activity relation;  animal;  Anthozoa;  chemistry;  clustered regularly interspaced short palindromic repeat;  drug development;  human;  metabolism;  molecular cloning;  rat;  signal transduction, Alkaloids;  Animals;  Anthozoa;  Cloning, Molecular;  Clustered Regularly Interspaced Short Palindromic Repeats;  Drug Discovery;  Humans;  Hydantoins;  Molecular Docking Simulation;  Rats;  Receptors, CXCR4;  Signal Transduction;  Structure-Activity Relationship",
    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. © 2020 Elsevier Inc."
}