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Molecules. 2018 Aug 10;23(8). pii: E1996. doi: 10.3390/molecules23081996.

Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells.

Author information

1
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. bartolomeo.bosco@unitn.it.
2
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy. andrea.defant@yahoo.it.
3
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. andrea.messina@unitn.it.
4
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. tania.incitti@gmail.com.
5
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. denise.sighel@unitn.it.
6
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy. denise.sighel@unitn.it.
7
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. angela.bozza@aulss8.veneto.it.
8
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. yari.ciribilli@unitn.it.
9
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. alberto.inga@unitn.it.
10
Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. simona.casarosa@unitn.it.
11
Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy. ines.mancini@unitn.it.

Abstract

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 13 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 13 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

KEYWORDS:

cell cycle arrest; endoreduplication; microwave-assisted synthesis; molecular docking; p53; reversine

PMID:
30103421
PMCID:
PMC6222518
DOI:
10.3390/molecules23081996
[Indexed for MEDLINE]
Free PMC Article

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