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

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 p...

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Autores principales: Rouchal, Michal, Rudolfová, Jana, Kryštof, Vladimír, Vojáčková, Veronika, Čmelík, Richard, Vícha, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657435/
https://www.ncbi.nlm.nih.gov/pubmed/34884480
http://dx.doi.org/10.3390/ijms222312675
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author Rouchal, Michal
Rudolfová, Jana
Kryštof, Vladimír
Vojáčková, Veronika
Čmelík, Richard
Vícha, Robert
author_facet Rouchal, Michal
Rudolfová, Jana
Kryštof, Vladimír
Vojáčková, Veronika
Čmelík, Richard
Vícha, Robert
author_sort Rouchal, Michal
collection PubMed
description 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.
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spelling pubmed-86574352021-12-10 Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity Rouchal, Michal Rudolfová, Jana Kryštof, Vladimír Vojáčková, Veronika Čmelík, Richard Vícha, Robert Int J Mol Sci Article 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. MDPI 2021-11-24 /pmc/articles/PMC8657435/ /pubmed/34884480 http://dx.doi.org/10.3390/ijms222312675 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rouchal, Michal
Rudolfová, Jana
Kryštof, Vladimír
Vojáčková, Veronika
Čmelík, Richard
Vícha, Robert
Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title_full Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title_fullStr Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title_full_unstemmed Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title_short Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
title_sort adamantane-substituted purines and their β-cyclodextrin complexes: synthesis and biological activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657435/
https://www.ncbi.nlm.nih.gov/pubmed/34884480
http://dx.doi.org/10.3390/ijms222312675
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