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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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12675 |
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| author | Michal Rouchal Jana Rudolfová Vladimír Kryštof Veronika Vojáčková Richard Čmelík Robert Vícha |
| author_facet | Michal Rouchal Jana Rudolfová Vladimír Kryštof Veronika Vojáčková Richard Čmelík Robert Vícha |
| author_sort | Michal Rouchal |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T04:53:37Z |
| format | Article |
| id | doaj.art-c111a4005877411e891420cb63a64840 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:37Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c111a4005877411e891420cb63a648402023-11-23T02:26:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231267510.3390/ijms222312675Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological ActivityMichal Rouchal0Jana Rudolfová1Vladimír Kryštof2Veronika Vojáčková3Richard Čmelík4Robert Vícha5Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech RepublicDepartment of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech RepublicDepartment of Experimental Biology, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech RepublicDepartment of Experimental Biology, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech RepublicInstitute of Analytical Chemistry of the Czech Academy of Sciences, Veveří 97, 602 00 Brno, Czech RepublicDepartment of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavrečkova 275, 760 01 Zlín, Czech RepublicCyclin-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.https://www.mdpi.com/1422-0067/22/23/12675adamantane2,6,9-trisubstituted purinecyclin-dependent kinasecytotoxicityβ-cyclodextrinmolecular docking |
| spellingShingle | Michal Rouchal Jana Rudolfová Vladimír Kryštof Veronika Vojáčková Richard Čmelík Robert Vícha Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity International Journal of Molecular Sciences adamantane 2,6,9-trisubstituted purine cyclin-dependent kinase cytotoxicity β-cyclodextrin molecular docking |
| 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 | adamantane 2,6,9-trisubstituted purine cyclin-dependent kinase cytotoxicity β-cyclodextrin molecular docking |
| url | https://www.mdpi.com/1422-0067/22/23/12675 |
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