2. Academic Validation
  3. Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies

Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies

  • J Med Chem. 2020 Feb 13;63(3):1199-1215. doi: 10.1021/acs.jmedchem.9b01554.
Cristina Galiana-Roselló 1 2,  Clara Aceves-Luquero 3,  Jorge González 1,  Álvaro Martínez-Camarena 1,  Ruth Villalonga 4,  Silvia Fernández de Mattos 3 5,  Concepción Soriano 6,  José Llinares 6,  Enrique García-España 1,  Priam Villalonga 3,  María Eugenia González-Rosende 2
Affiliations

Affiliations

  • 1 Instituto de Ciencia Molecular (ICMol), Departamento de Química Inorgánica , Universidad de Valencia , Paterna, 46980 Valencia , Spain.
  • 2 Departamento de Farmacia, Facultad de Ciencias de la Salud , Universidad CEU Cardenal Herrera, C/ Ramón y Cajal, s/n , Alfara del Patriarca, 46115 Valencia , Spain.
  • 3 Cancer Cell Biology Laboratory, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS) , Universitat de les Illes Balears, and Institut d'Investigació Sanitària Illes Balears (IdISBa) , Palma, 07122 Illes Balears , Spain.
  • 4 Departament de Química , Universitat de les llles Balears , Palma, 07122 Illes Balears , Spain.
  • 5 Departament de Biologia Fonamental , Universitat de les Illes Balears , Palma, 07122 Illes Balears , Spain.
  • 6 Departamento de Química Orgánica , Universidad de Valencia , C/Dr. Moliner s/n , Burjassot, 46100 Valencia , Spain.
PMID: 31935092 DOI: 10.1021/acs.jmedchem.9b01554
Abstract

In vitro viability assays against a representative panel of human Cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and Apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL2+ stability constant values in solution, strongly supports their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise structure-activity relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating Anticancer agents that deserves further development.

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