Abstract
Pteridines are bicyclic heterocyclic compounds with a pyrazino[2,3-d]pyrimidine nucleus that have shown a wide range of therapeutic utilities. Concretely, 4-aminopteridine derivatives have demonstrated both anti-inflammatory and anti-cancer properties, and some of them, such as methotrexate, are profusely used in medical practice. We have recently synthesized and tested the biological activity of a novel series of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines, finding that they present anti-inflammatory properties, as they were able to inhibit in vitro the production of pro-inflammatory cytokines TNF-α and IL-6. Now, we have evaluated the anti-tumor potential of these compounds on HL-60 and K562 leukemia cell lines. Cells growing at exponential rate were exposed to decreasing doses of each compound, from 50 to 0.39 μM, for 24, 48, and 72 h. Cell viability was tested by MTT assay and cell death fashion determined by annexin V/propidium iodide assay. The cytotoxicity of the compounds was determined in differentiated macrophage-like HL-60 cells and in human peripheral blood mononuclear cells to evaluate the potential side effects on quiescent tumor cells and normal cells, respectively. Among the series, compounds 1a, 1b, 1g, 1j, and 1k showed anti-proliferative activity. Compounds 1j and 1k were active against both HL-60 and K562 cells, with a lower IC50 against HL-60 cells. Compounds 1a, 1b, and 1g had a great cytotoxic activity against HL-60, but they were far less potent against K562 cells. None had side effects in differentiated tumor cells or in human peripheral blood mononuclear cells. In conclusion, our results demonstrate that some compounds of this series of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines have anti-cancer properties in vitro.
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Funding
This study was partially supported by a grant from the Fundación Séneca of the Comunidad Autónoma de la Región de Murcia (project 19249/PI/14), Spain. Violeta Carmona-Martínez was supported by the Dirección General de Investigación Científica y Técnica (Grant EJ-2014-A-95803), Spain.
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AJRA conceived and designed the experimental plan, performed experiments, analyzed the data, and wrote the manuscript. VCM performed experiments, analyzed the data and wrote the manuscript. AG synthesized and provided the new organic compounds and wrote the manuscript. JG analyzed data. MME wrote the manuscript. PGP provided the necessary facilities and wrote the manuscript. All authors read and approved the manuscript.
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The ethics committees (Comité Ético de Investigación Clínica del Hospital Universitario Virgen de la Arrixaca, and Comité de Bioética de la Universidad de Murcia) approved the study protocol according to the 1975 Declaration of Helsinki.
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The authors declare that they have no conflict of interest.
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Ruiz-Alcaraz, A.J., Carmona-Martínez, V., Guirado, A. et al. Anti-leukemia activity of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines. Naunyn-Schmiedeberg's Arch Pharmacol 392, 219–227 (2019). https://doi.org/10.1007/s00210-018-1587-0
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DOI: https://doi.org/10.1007/s00210-018-1587-0