Abstract
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug’s solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.
Highlights
Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that play a crucial role in controlling the cell division cycle in all eukaryotic cells
A novel series of 2,6,9-trisubstituted purines bearing the adamantane moiety was prepared with a three-step procedure outlined in Schemes 1 and 2
Previous studies demonstrated that substituting purine at position 6 with adamantylamine would switch off the inhibition activity towards CDK1 and CDK2, we reached IC50(CDK2/E) = 0.21 ± 0.02 μM for adamatylated purine 4b, which is even lower than that of its parent, bohemine 4k
Summary
Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that play a crucial role in controlling the cell division cycle in all eukaryotic cells. It was found that the excessive activity of cyclins or loss of expression of endogenous CDK protein inhibitors (Cip/Kip or INK4), which results in the deregulation of CDKs activity, is frequently observed in human malignancies. This initiated extensive search for the low-molecular-weight inhibitors of CDKs [2,3]. In 2015, the low-molecular-weight inhibitor of CDK4 and CDK6 palbociclib was approved by the United States Food and Drug Administration for the treatment of breast cancer in clinical use This drug was followed by the two CDK4/6 inhibitors, ribociclib and abemaciclib [5]
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