Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity

• Published in: International journal of molecular sciences Vol. 22; no. 23; p. 12675
• Main Authors: Rouchal, Michal, Rudolfová, Jana, Kryštof, Vladimír, Vojáčková, Veronika, Čmelík, Richard, Vícha, Robert
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-11-2021; MDPI
• Subjects: 2,6,9-trisubstituted purine; adamantane; Adamantane - chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; beta-Cyclodextrins - chemistry; Binding; Biological activity; Cell division; Chemistry; Chromatography; Cyclin E; cyclin-dependent kinase; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-dependent kinases; Cyclodextrins; cytotoxicity; Experiments; Humans; K562 Cells; Kinases; MCF-7 Cells; molecular docking; NMR; Nuclear magnetic resonance; Polarity; Protein Kinase Inhibitors - pharmacology; Purines; Purines - chemistry; Solubility; Structure-Activity Relationship; β-Cyclodextrin; 2,6,9-trisubstituted purine; adamantane; molecular docking; cyclin-dependent kinase; β-cyclodextrin; cytotoxicity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312675

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.