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

• Published in: Molecules (Basel, Switzerland) Vol. 23; no. 8; p. 1996
• Main Authors: Bosco, Bartolomeo, Defant, Andrea, Messina, Andrea, Incitti, Tania, Sighel, Denise, Bozza, Angela, Ciribilli, Yari, Inga, Alberto, Casarosa, Simona, Mancini, Ines
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-08-2018; MDPI
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biotechnology; Breast cancer; Breast Neoplasms; Cell cycle; cell cycle arrest; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemistry Techniques, Synthetic; Chloroform; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms; Cytotoxicity; Density functional theory; Docking; endoreduplication; Female; Humans; Male; microwave-assisted synthesis; Microwaves; molecular docking; Molecular Structure; N6-methyladenosine; p53; p53 Protein; Polyploidy; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; reversine; Solvents; Structure-Activity Relationship; Substitutes; Tautomers; Tumor cell lines; microwave-assisted synthesis; reversine; molecular docking; cell cycle arrest; endoreduplication; p53
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23081996

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
6-cyclohexyl-
6-methyl-
2-phenyl-7
-purine-2,6-diamine (
), 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 H
(9) tautomer resulted more stable than the H
(7) form, but the most stable conformations changed in different solvents. Molecules
⁻
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
⁻
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.