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Adamantane-Substituted Purines and Their ß-Cyclodextrin Complexes: Synthesis and Biological Activity.
Rouchal, Michal; Rudolfová, Jana; Krystof, Vladimír; Vojácková, Veronika; Cmelík, Richard; Vícha, Robert.
Affiliation
  • Rouchal M; Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavreckova 275, 760 01 Zlín, Czech Republic.
  • Rudolfová J; Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavreckova 275, 760 01 Zlín, Czech Republic.
  • Krystof V; Department of Experimental Biology, Palacký University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
  • Vojácková V; Department of Experimental Biology, Palacký University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
  • Cmelík R; Institute of Analytical Chemistry of the Czech Academy of Sciences, Veverí 97, 602 00 Brno, Czech Republic.
  • Vícha R; Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavreckova 275, 760 01 Zlín, Czech Republic.
Int J Mol Sci ; 22(23)2021 Nov 24.
Article in En | MEDLINE | ID: mdl-34884480
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 ß-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 ß-CD.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Purines / Adamantane / Beta-Cyclodextrins / Protein Kinase Inhibitors / Cyclin-Dependent Kinase 2 / Antineoplastic Agents Limits: Humans Language: En Journal: Int J Mol Sci Year: 2021 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Purines / Adamantane / Beta-Cyclodextrins / Protein Kinase Inhibitors / Cyclin-Dependent Kinase 2 / Antineoplastic Agents Limits: Humans Language: En Journal: Int J Mol Sci Year: 2021 Document type: Article Affiliation country: