Adamantane-Substituted Purines and Their ß-Cyclodextrin Complexes: Synthesis and Biological Activity.
Int J Mol Sci
; 22(23)2021 Nov 24.
Article
en 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Purinas
/
Adamantano
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Beta-Ciclodextrinas
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Inhibidores de Proteínas Quinasas
/
Quinasa 2 Dependiente de la Ciclina
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2021
Tipo del documento:
Article
País de afiliación:
República Checa
Pais de publicación:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND