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 1–3 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 1–3 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.
Highlights
Pluripotent cells play a relevant role in regenerative medicine, due to their capability of differentiating into many cell types
The design of the molecules 1–3 (Figure 1) was performed via structure selection based on docking calculations, considering both energy values and interactions of the complexes between the molecules and the two known target proteins of reversine, Aurora-B kinase and Monopolar Spindle 1 (Mps1)
We evaluated the growth inhibition effect of the synthetic products in comparison to reversine on two cancer cell lines: the MCF-7 breast cancer (MCF-7 Vector) line and the HCT116 colorectal cancer line
Summary
Pluripotent cells play a relevant role in regenerative medicine, due to their capability of differentiating into many cell types. Pluripotency can be achieved in vitro, by over-expressing specific genes or by chemical induction, using a combination of synthetic molecules [1]. Among them the 2,6-diamino-substituted purine reversine (N6-cyclohexyl-N2-(4-morpholinophenyl)7H-purine-2,6-diamine), firstly synthesized by Schultz and coworkers [2], is a promising molecule. It induces de-differentiation of C2C12 murine myoblasts and allows their subsequent differentiation in adipocytes, osteoblasts [3], neural progenitor-like cells [4] and cardiomyocytes [5], under specific conditions. Reversine is an inhibitor of Aurora kinases, Cyclin Dependent Kinases
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